A Randomised Phase II Trial to Evaluate the Feasibility of Radiotherapy Dose Escalation, Facilitated by Intensity-Modulated Arc Radiotherapy Techniques, in High-Risk Neuroblastoma.

BACKGROUND AND PURPOSE: For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. MATERIALS AND METHODS: Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. RESULTS: Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0-36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7-35.9 Gy). CONCLUSION: IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial.

Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS.

Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently been reported in patients with primary progressive MS (PPMS) (Højsgaard Chow et al., 2021). In order to further analyze the immunological treatment response we investigated the systemic and intrathecal immunological effects of dimethyl fumarate (DMF) treatment in 50 patients with PPMS who participated in a 48-week randomized controlled trial with dimethyl fumarate vs placebo. We found substantial systemic immunomodulatory effects of DMF treatment comparable with those observed in patients with RRMS. However, intrathecal effects were limited and restricted to CD4+ T cells presumably resulting in higher concentrations of intrathecal IL-7.

Improvements in pain, medication use and quality of life in onabotulinumtoxinA-resistant chronic migraine patients following erenumab treatment - real world outcomes.

BACKGROUND: The CGRP antagonists offer a novel therapeutic approach in migraine. Their utility in patients with severe forms of chronic migraine is a subject of particular interest. We present outcomes of 9 months of erenumab treatment in a cohort of patients with difficult-to-control chronic migraine, all of whom had prior unsatisfactory response to onabotulinumtoxinA. METHODS: We offered erenumab to 98 patients with a prior unsatisfactory response to onabotulinumtoxinA. Eighty of 98 had trialled greater occipital nerve injections (82%), 32/98 peripheral neurostimulation (33%) and 18/98 intravenous dihydroergotamine (18%). Thirty eight of 98 (39%) met the definition of triptan overuse and 43/98 (44%) analgesic overuse. All patients met the EHF criteria for 'resistant migraine'. Outcome measures (recorded monthly) included days with headache limiting activities of daily living ("red"), not limiting ("amber"), headache free ("green"), and requiring triptans or other analgesics. Quality of life scores - headache impact test 6 (HIT-6), patient health questionnaire 9 (PHQ-9) and pain disability index (PDI) - were also measured. RESULTS: Mean number of red days improved by - 6.4 days (SE 0.67, 95%CI - 7.7 to - 5.1, p=0.001) at 3 months; - 6.8 days (SE 0.96, 95%CI - 8.80 to - 4.9, p=0.001) at 6 months and - 6.5 days (SE 0.86, 95%CI - 8.3 to - 4.8, p=0.001) at 9 months. Repeated measures ANOVA confirmed improvements in the number of red (p=0.001), green (p=0.001), triptan (p=0.001) and painkiller days (p=0.001) as well as scores of the HIT-6 (p=0.001), PHQ-9 (p=0.001), and PDI (p=0.001) across the duration of study. CONCLUSION: We observed improvements in pain, medication use and quality of life in onabotulinumtoxinA-resistant chronic migraine patients following erenumab treatment.

Higher levels of social and material deprivation are associated with higher rates of influenza-like illness-related emergency department visits: Edmonton, Alberta, 2004-2014.

OBJECTIVES: Neighbourhood-level deprivation is associated with hospitalization related to respiratory infections; however, hospitalizations exclude many who seek care with less severe respiratory illnesses. Another major seasonal contributor to respiratory illness-associated healthcare burdens are influenza-like illness (ILI)-related emergency department (ED) visits. We investigated associations between area-level social and material deprivation and ILI-related ED use. STUDY DESIGN: This is a retrospective ecological study. METHODS: We linked ILI-related ED visit data (2004-2014) for Edmonton, Alberta to a Canadian area-level material and social deprivation index, categorizing deprivation into quintiles. Using a multivariable Poisson model with log population as the offset, we modelled the relationship between visit rates and material and social deprivation adjusting for week and season, age, sex and the interaction between age and sex. RESULTS: We included 67,585 ILI-related ED visits, representing 1075.5 (95% confidence interval (CI) = 1067.4-1083.6) visits per 100,000 person-years. ILI-related visit rates increased as each of material and social deprivation increased; increases were slightly greater for material deprivation. Comparing the most deprived quintile to the least deprived quintile: for material deprivation, ILI-related ED visit rates were two times higher (rate ratio (RR) = 2.00, 95% CI = 1.96-2.05); and, for social deprivation, one-and-a-half times higher (RR = 1.47, 95% CI = 1.44-1.51). CONCLUSIONS: Higher area-level material and social deprivation were associated with higher ILI-related ED visit rates. These findings can be used to identify areas that may need additional public health and healthcare resources and to improve targeting of prevention strategies. Understanding differentials in healthcare use such as this may be especially relevant to ensuring equity of outcomes for pandemic preparedness planning.

Comment on: "A novel approach to peatlands as archives of total cumulative spatial pollution loads from atmospheric deposition of airborne elements complementary to EMEP data: Priority pollutants (Pb, Cd, Hg)" by Ewa Miszczak, Sebastian Stefaniak, Adam Michczynski, Eiliv Steinnes and Irena Twardowska.

A recent paper by Miszczak et al. (2020) examines metal contamination of mires in Poland and Norway. The authors conclude that lead (Pb) records in ombrotrophic peatlands cannot be used to reconstruct the chronological history of anthropogenic activities due to post-depositional mobility of the metal. We contest this general conclusion which stands in contrast with a significant body of literature demonstrating that Pb is largely immobile in the vast majority of ombrotrophic peatlands. Our aim is to reaffirm the crucial contribution that peat records have made to our knowledge of atmospheric Pb contamination. In addition, we reiterate the necessity of following established protocols to produce reliable records of anthropogenic Pb contamination in environmental archives.

Predicting influenza-like illness-related emergency department visits by modelling spatio-temporal syndromic surveillance data.

Predicting the magnitude of the annual seasonal peak in influenza-like illness (ILI)-related emergency department (ED) visit volumes can inform the decision to open influenza care clinics (ICCs), which can mitigate pressure at the ED. Using ILI-related ED visit data from the Alberta Real Time Syndromic Surveillance Net for Edmonton, Alberta, Canada, we developed (training data, 1 August 2004-31 July 2008) and tested (testing data, 1 August 2008-19 February 2014) spatio-temporal statistical prediction models of daily ILI-related ED visits to estimate high visit volumes 3 days in advance. Our Main Model, based on a generalised linear mixed model with random intercept, incorporated prediction residuals over 14 days and captured increases in observed volume ahead of peaks. During seasonal influenza periods, our Main Model predicted volumes within ±30% of observed volumes for 67%-82% of high-volume days and within 0.3%-21% of observed seasonal peak volumes. Model predictions were not as successful during the 2009 H1N1 pandemic. Our model can provide early warning of increases in ILI-related ED visit volumes during seasonal influenza periods of differing intensities. These predictions may be used to support public health decisions, such as if and when to open ICCs, during seasonal influenza epidemics.

Hyperparathyroidism in pregnancy and 99mTc-MIBI scintigraphy.

INTRODUCTION: Primary hyperparathyroidism (PHPT) during pregnancy can be responsible for serious maternal and foetal complications and should be treated by elective low-risk, minimally invasive surgery. Preoperative assessment of hyperfunctioning parathyroid glands is classically based on high-resolution neck ultrasound (US) and 99mTc-sestamibi/123I scintigraphy. However, administration of any radiopharmaceutical during pregnancy must be limited and justified and US alone may be sufficient to localize an abnormal parathyroid gland. CASE REPORT: We report the case of a 4-month pregnant woman with severe primary hyperparathyroidism, in whom US failed to localize the abnormal parathyroid gland. 99mTc-sestamibi scintigraphy was performed in preference to 18-fluorocholine (FCH)-PET/CT on the basis of a multidisciplinary decision. As 99mTc-MIBI demonstrated an hyperfunctioning right inferior parathyroid, 123I was not administered. A large right paravertebral parathyroid adenoma was successfully removed, as confirmed by decreased postoperative serum parathyroid hormone and calcium levels. The eutrophic newborn infant was delivered at term, with normal serum calcium and TSH levels. DISCUSSION: In pregnant women with primary hyperparathyroidism, US alone may be sufficient when it localizes the abnormal parathyroid gland, allowing elective low-risk minimally invasive surgery. Otherwise, a multidisciplinary approach is mandatory to select the radiopharmaceutical that can be safely used to identify the hyperfunctioning parathyroid gland with minimal risks for the foetus.

Identifying the barriers and facilitators for homeless people to achieve good oral health.

OBJECTIVE: A qualitative exploration of the barriers and facilitators for people experiencing homelessness achieving good oral health. PARTICIPANTS: Adults using two homeless centres in Leeds. METHODS: Focus group discussions were convened with homeless people using support services. Both an inductive and deductive approach to data analysis was taken. Themes were identified and then a framework applied to analysis using Nvivo software. RESULTS: Three focus group discussions with 16 participants were conducted with people experiencing homelessness. The barriers identified were insufficient information on local dental services, negative attitudes of oral health professionals, low priority of dental care, anxiety and cost of dental treatments. Facilitators included single dental appointments, accessible dental locations and being treated with respect. CONCLUSIONS: Despite the barriers that prevent people experiencing homelessness from maintaining and improving their oral health, the participants were aware that they needed oral healthcare and requested that dental services were made available to them and were accessible in line with their socioeconomic status and needs.

Prognostic value of functional tumor burden on 68Ga-DOTATOC PET/CT in patients with pancreatic neuro-endocrine tumors.

Despite their relative quiescence, pancreatic neuro-endocrine tumors (pNET) can correspond to various presentations and outcomes. Several prognostic factors have been identified, including maximal standardized uptake value of the most intense focus (maxSUVmax) on Positron Emission Tomography (PET) with a somatostatin analogue. Herein, we investigate the prognostic value on progression free-survival of the total functional tumor volume (TFTV) measured by 68Ga-DOTATOC PET. From patients who underwent 68Ga-DOTATOC PET from 2008 to 2014, we selected consecutive patients with G1 or G2 pNET (2010 World Health Organization classification), at least one abnormal focus on PET and available follow-up data. TFTV was computed by summing the volumes of all pathological foci, delineated use of 41% of its SUVmax for each threshold focus. Fifty patients were included. During the follow-up period, 33 patients had stable or responsive disease (66%; median duration 28.5 months; range 6.3-77.7 months) and 17 patients experienced disease progression (34%; median progression time 21 months; range 6.7-44.7 months). Median PFS was 43.5 months. The best TFTV cut-off for predicting progression within 24 months was 13.8 cm3. Multivariate analysis determined that TFTV greater than 13.8 cm3 was the only criterion considered a significant risk factor for tumor progression (HR 2.9; p=0.0003). A significant difference in PFS was observed for TFTV (<13.8 vs. ≥ 13.8 cm3: median not reached vs. 25 months; p=0.0001). Our study suggests that 68Ga-DOTATOC TFTV measured on PET images is a valuable prognostic biomarker in patients with well-differentiated pNETs of all stages.

Unravelling species boundaries in the Aspergillus viridinutans complex (section Fumigati): opportunistic human and animal pathogens capable of interspecific hybridization.

Although Aspergillus fumigatus is the major agent of invasive aspergillosis, an increasing number of infections are caused by its cryptic species, especially A. lentulus and the A. viridinutans species complex (AVSC). Their identification is clinically relevant because of antifungal drug resistance and refractory infections. Species boundaries in the AVSC are unresolved since most species have uniform morphology and produce interspecific hybrids in vitro. Clinical and environmental strains from six continents (n = 110) were characterized by DNA sequencing of four to six loci. Biological compatibilities were tested within and between major phylogenetic clades, and ascospore morphology was characterised. Species delimitation methods based on the multispecies coalescent model (MSC) supported recognition of ten species including one new species. Four species are confirmed opportunistic pathogens; A. udagawae followed by A. felis and A. pseudoviridinutans are known from opportunistic human infections, while A. felis followed by A. udagawae and A. wyomingensis are agents of feline sino-orbital aspergillosis. Recently described human-pathogenic species A. parafelis and A. pseudofelis are synonymized with A. felis and an epitype is designated for A. udagawae. Intraspecific mating assay showed that only a few of the heterothallic species can readily generate sexual morphs in vitro. Interspecific mating assays revealed that five different species combinations were biologically compatible. Hybrid ascospores had atypical surface ornamentation and significantly different dimensions compared to parental species. This suggests that species limits in the AVSC are maintained by both pre- and post-zygotic barriers and these species display a great potential for rapid adaptation and modulation of virulence. This study highlights that a sufficient number of strains representing genetic diversity within a species is essential for meaningful species boundaries delimitation in cryptic species complexes. MSC-based delimitation methods are robust and suitable tools for evaluation of boundaries between these species.

[PET/CT and biochemical recurrence of prostate adenocarcinoma: Added value of 68Ga-PSMA-11 when 18F-fluorocholine is non-contributive]. / TEP/TDM et récidive biologique d'adénocarcinome prostatique : apport du 68Ga-PSMA-11 lorsque la 18F-fluorocholine n'est pas contributive.

INTRODUCTION: Since April 201, we have introduced PET/CT using a ligand of prostate-specific membrane antigen labeled with gallium-68 (PSMA-11). We aimed to evaluate its positivity rate and impact in patients presenting biochemical recurrence of prostate cancer whose 18F-fluorocholine (FCH) PET/CT was non-contributive. PATIENTS AND METHOD: Patients were prospectively included between April and December 2016. PET/CT was performed 60min after injection of 2MBq/kg of body mass of 68Ga-PSMA-11. Three anatomical areas were considered: prostatic lodge, pelvic lymph nodes and distant locations. The impact of PSMA-11 PET/CT was assessed by comparing changes in therapeutic strategy decided during multidisciplinary meeting. RESULTS: Thirty-three patients were included. The mean PSA serum level measured on the month of the PSMA-11 PET/CT was 2,8ng/mL. Twenty-five (76%) PSMA-11 PET/CT were positive, 7 (21%) negative and 1 (3%) equivocal. Of 11 patients whose FCH PET/CT showed equivocal foci, PSMA-11 PET/CT confirmed those foci in 5 cases. Follow-up was available for 18 patients (55%). PSMA-11 PET/CT results led to a change in management in 12 patients (67%). CONCLUSION: 68Ga-PSMA-11 PET/CT is useful in detecting recurrence of prostate cancer, by identifying residual disease which was not detected on other imaging modalities and by changing management of 2 patients out of 3. LEVEL OF EVIDENCE: 5.

Quantum molecular motion in the mixed ion-radical complex, [(H2O)(H2S)].

The cation dimer of water and hydrogen sulfide, [(H2O)(H2S)]+, serves as a fundamental model for the oxidation chemistry of H2S. The known oxidative metabolism of H2S by biological species in sulfur-rich environments has motivated the study of the inherent properties of this benchmark complex, with possible mechanistic implications for modern water oxidation chemistry. The low-energy isomer of this open-shell ion is a proton-transferred (PT) structure, H3O+SH˙. An alternative PT structure, H3S+OH˙, and a hemibonded (HB) isomer, [H2O·SH2]+, are also stable isomers, placing this complex intermediate to known (H2O)2+ (PT) and (H2S)2+ (HB) limiting regimes. This intermediate character suggested the possibility of unique molecular motion, even in the vibrational ground state. Path integral molecular dynamics and anharmonic vibrational spectroscopy simulations have been performed in this study, in order to understand the inherent quantum molecular motion of this complex. The resulting structural distributions were found to deviate significantly from both classical and harmonic analyses, including the observation of large-amplitude anharmonic motion of the central proton and nearly free rotation of the terminal hydrogens. The predicted vibrational spectra are particularly unique and suggest characteristic signatures of the strong electronic interactions and anharmonic vibrational mode couplings in this radical cation.

Effect of crowding and confinement on first-passage times: A model study.

We study the "color dynamics" of a hard-disk fluid confined in an annulus, as well as the corresponding hard-sphere system in three dimensions, using event-driven simulation in order to explore the effect of confinement and self-crowding on the search for targets. We compute the mean first-passage times (MFPTs) of red particles transiting from the outer to the inner boundary as well as those of blue particles passing from the inner to the outer boundary for different packing fractions and geometries. In the steady state the reaction rate, defined as the rate of collision of red particles with the inner boundary, is inversely proportional to the sum of the MFPTs. The reaction rate is wall mediated (ballistic) at low densities and diffusion controlled at higher densities and displays a maximum at intermediate densities. At moderate to high densities, the presence of layering has a strong influence on the search process. The numerical results for the reaction rate and MFPTs are compared with a ballistic model at low densities and a Smoluchowski approach with uniform diffusivities at higher densities. We discuss the reasons for the limited validity of the theoretical approaches. The maximum in the reaction rate is qualitatively well rendered by a Bosanquet-like approach that interpolates between the two regimes. Finally, we compute the position-dependent diffusivity from the MFPTs and observe that it is out of phase with the radial density.

Best sensitivity of 18F-FDOPA PET/CT to detect metastasis in one case of neuroendocrine tumour of the ileum. / Mejor rendimiento de la PET/TC con 18F-FDOPA para la detección de metástasis de un tumor neuroendocrino del íleon.

Neuroendocrine tumours (NET) are heterogeneous and frequently spread over the body, making their imaging difficult. With this aim, nuclear medicine imaging, using PET or SPECT with different tracers, has been proposed for decades, but there is currently no consensus on the most appropriate technique, even when only considering gastrointestinal NET. The case is presented of a 67year old woman with a well differentiated NET of the ileum with suspected recurrence, which was not detected by any imaging technique except 18F-FDOPA PET/CT. Subsequent follow up showed disease progression, which confirmed the true positivity of 18F-FDOPA. Using this case, we discuss and compare different radiotracers for the diagnosis of gastrointestinal NET, focusing on those embryologically originating from the mid-gut.

Nano- and micro-patterning biotemplated magnetic CoPt arrays.

Patterned thin-films of magnetic nanoparticles (MNPs) can be used to make: surfaces for manipulating and sorting cells, sensors, 2D spin-ices and high-density data storage devices. Conventional manufacture of patterned magnetic thin-films is not environmentally friendly because it uses high temperatures (hundreds of degrees Celsius) and high vacuum, which requires expensive specialised equipment. To tackle these issues, we have taken inspiration from nature to create environmentally friendly patterns of ferromagnetic CoPt using a biotemplating peptide under mild conditions and simple apparatus. Nano-patterning via interference lithography (IL) and micro-patterning using micro-contact printing (µCP) were used to create a peptide resistant mask onto a gold surface under ambient conditions. We redesigned a biotemplating peptide (CGSGKTHEIHSPLLHK) to self-assemble onto gold surfaces, and mineralised the patterns with CoPt at 18 °C in water. Ferromagnetic CoPt is biotemplated by the immobilised peptides, and the patterned MNPs maintain stable magnetic domains. This bioinspired study offers an ecological route towards developing biotemplated magnetic thin-films for use in applications such as sensing, cell manipulation and data storage.

Expression and activity of NOD1 and NOD2/RIPK2 signalling in mononuclear cells from patients with rheumatoid arthritis.

OBJECTIVES: The aim of this study was to analyse the expression and function of nucleotide-binding oligomerization domain (NOD)1 and NOD2 in isolated cells of patients with rheumatoid arthritis (RA). METHOD: mRNA expression levels of NOD1, NOD2, and receptor-interacting serine/threonine kinase 2 (RIPK2) genes were determined by quantitative polymerase chain reaction (qPCR) in peripheral blood mononuclear cells (PBMCs) and synovial fluid T cells (SFTCs) isolated from RA and osteoarthritis (OA) patients. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA) in plasma and cell culture supernatants. The stimulatory effect of RA SF was assessed by an in-vitro NOD2 activation assay using nuclear factor kappa B (NF-κB) luciferase-transfected cells. RESULTS: A significantly higher level of NOD2 and RIPK2 mRNA expression, but not NOD1, was observed on PBMCs and SFTCs isolated from RA patients compared to the OA control group. In addition, the NOD2 pathway up-regulation was functional, as stimulation of PBMCs with muramyl dipeptide (MDP) induced the production of higher amounts of tumour necrosis factor (TNF)-α, interleukin (IL)-8, and IL-1ß compared with OA PBMCs. Incubation of PBMCs from healthy donors with recombinant TNF-α or RA serum induced the expression of NOD2 mRNA. Finally, SF isolated from RA patients is able to activate the NF-κB signalling pathway in HEK293T-transfected cells in a NOD2-dependent manner. CONCLUSIONS: Our findings suggest that NOD2/RIPK2 signalling is up-regulated in immune cells of RA patients. Moreover, it seems that there is a NOD2 agonist in the SF of RA patients. Therefore, NOD2/RIPK2 activation can modulate the innate immune response and may play a role in the perpetuation of the inflammatory response in RA.

First-Passage Times in d-Dimensional Heterogeneous Media.

Although there are many theoretical studies of the mean first-passage time (MFPT), most neglect the diffusive heterogeneity of real systems. We present exact analytical expressions for the MFPT and residence times of a pointlike particle diffusing in a spherically symmetric d-dimensional heterogeneous system composed of two concentric media with different diffusion coefficients with an absorbing inner boundary (target) and a reflecting outer boundary. By varying the convention, e.g., Ito, Stratonovich, or isothermal, chosen to interpret the overdamped Langevin equation with multiplicative noise describing the diffusion process, we find different predictions and counterintuitive results for the residence time in the outer region and hence for the MFPT, while the residence time in the inner region is independent of the convention. This convention dependence of residence times and the MFPT could provide insights about the heterogeneous diffusion in a cell or in a tumor, or for animal and insect searches inside their home range.

Cascading blockages in channel bundles.

Flow in channel networks may involve a redistribution of flux following the blockage or failure of an individual link. Here we consider a simplified model consisting of N(c) parallel channels conveying a particulate flux. Particles enter these channels according to a homogeneous Poisson process and an individual channel blocks if more than N particles are simultaneously present. The behavior of the composite system depends strongly on how the flux of entering particles is redistributed following a blockage. We consider two cases. In the first, the intensity on each open channel remains constant while in the second the total intensity is evenly redistributed over the open channels. We obtain exact results for arbitrary N(c) and N for a system of independent channels and for arbitrary N(c) and N=1 for coupled channels. For N>1 we present approximate analytical as well as numerical results. Independent channels block at a decreasing rate due to a simple combinatorial effect, while for coupled channels the interval between successive blockages remains constant for N=1 but decreases for N>1. This accelerating cascade is due to the nonlinear dependence of the mean blocking time of a single channel on the entering particle flux that more than compensates for the decrease in the number of active channels.