Stereotactic body radiotherapy of central lung tumours using a 1.5 T MR-linac: First clinical experiences.

Background: MRI-guidance may aid better discrimination between Organs at Risk (OARs) and target volumes in proximity of the mediastinum. We report the first clinical experiences with Stereotactic Body Radiotherapy (SBRT) of (ultra)central lung tumours on a 1.5 T MR-linac. Materials and Methods: Patients with an (ultra)central lung tumour were selected for MR-linac based SBRT treatment. A T2-weighted 3D sequence MRI acquired during free breathing was used for daily plan adaption. Prior to each fraction, contours of Internal Target Volume (ITV) and OARs were deformably propagated and amended by a radiation oncologist. Inter-fractional changes in volumes and coverage of target volumes as well as doses in OARs were evaluated in offline and online treatment plans. Results: Ten patients were treated and completed 60 Gy in 8 or 12 fractions. In total 104 fractions were delivered. The median time in the treatment room was 41 min with a median beam-on time of 8.9 min. No grade ≥3 acute toxicity was observed. In two patients, the ITV significantly decreased during treatment (58 % and 37 %, respectively) due to tumour shrinkage. In the other patients, 81 % of online ITVs were within ±15 % of the volume of fraction 1. Comparison with the pre-treatment plan showed that ITV coverage of the online plan was similar in 52 % and improved in 34 % of cases. Adaptation to meet OAR constraints, led to decreased ITV coverage in 14 %. Conclusions: We describe the workflow for MR-guided Radiotherapy and the feasibility of using 1.5 T MR-linac for SBRT of (ultra) central lung tumours.

The evolution of multiple colour mechanisms is correlated with diversification in sunbirds (Nectariniidae).

How and why certain groups become speciose is a key question in evolutionary biology. Novel traits that enable diversification by opening new ecological niches are likely important mechanisms. However, ornamental traits can also promote diversification by opening up novel sensory niches and thereby creating novel inter-specific interactions. More specifically, ornamental colours may enable more precise and/or easier species recognition, and may act as key innovations by increasing the number of species-specific patterns and promoting diversification. While the influence of colouration on diversification is well-studied, the influence of the mechanisms that produce those colours (e.g. pigmentary, nanostructural) is less so, even though the ontogeny and evolution of these mechanisms differ. We estimated a new phylogenetic tree for 121 sunbird species and combined colour data of 106 species with a range of phylogenetic tools to test the hypothesis that the evolution of novel colour mechanisms increases diversification in sunbirds, one of the most colourful bird clades. Results suggest that (1) the evolution of novel colour mechanisms expands the visual sensory niche, increasing the number of achievable colours. (2) Structural colouration diverges more readily across the body than pigment-based colouration, enabling an increase in colour complexity. (3) Novel colour mechanisms might minimize trade-offs between natural and sexual selection such that colour can function both as camouflage and conspicuous signal. (4) Despite structural colours being more colourful and mobile, only melanin-based colouration is positively correlated with net diversification. Together, these findings explain why colour distances increase with increasing number of sympatric species, even though packing of colour space would predict otherwise.

Dosimetric evaluation of off-axis fields and angular transmission for the 1.5 T MR-linac.

Objective.GPU-oriented Monte Carlo dose (GPUMCD) is a fast dose calculation algorithm used for treatment planning on the Unity MR-linac. Treatments for the MR-linac must be calculated quickly and accurately, and must account for two important MR-linac aspects: off-axis positions and angular transmission through the cryostat, couch and MR-coils. Therefore, the aim of this research is to quantify the system-related errors for GPUMCD calculations over the range of clinically-relevant field configurations and gantry angles.Approach.Dose profiles (crossline, inline and PDD) were measured and calculated for varying field sizes, off-axis positions and depths. Eleven different (off-axis) positions were included. The angular transmission was investigated by measuring and calculating the transmission for multiple angles, taking the cryostat, couch and coils into account.Main results.Differences between absolute point doses were found to be within 1.7% for field sizes 2 × 2 cm2and larger. The relative dose profiles in the crossline, inline and PDD direction illustrated maximum mean dose differences of 0.9pp, 0.8pp and 0.7pp ofDmaxin the central region for field sizes 2 × 2 cm2and larger. The 1 × 1 cm2field size showed larger dosimetric errors for absolute point doses and relative dose profiles. The maximum mean DTA in the penumbra was 0.7 mm. The mean difference in angular transmission ranged from -0.33% ± 0.60% to 0.27% ± 0.91% using three treatment machines. Additionally, 77.1%-93.7% of the datapoints remained within 1% transmission difference. The largest transmission differences were present at the edges of the table.Significance.This research showed that the GPUMCD algorithm provides reliable dose calculations with a low uncertainty for field sizes 2 × 2 cm2and larger, focusing on off-axis fields and angular transmission.

Survival Outcomes Following Discontinuation of Ipilimumab and Nivolumab for Advanced Melanoma in a Population-based Cohort.

AIMS: Induction ipilimumab and nivolumab followed by maintenance nivolumab improve overall survival compared with ipilimumab alone in patients with advanced melanoma, but immune-related adverse events (irAE) occur commonly. The need for induction discontinuation because of irAE and the relationship between irAE and survival in non-trials patients are unclear. MATERIALS AND METHODS: Patients with unresectable stage III-IV melanoma receiving first-line combination immunotherapy at one of six centres between December 2017 and February 2020 outside of trials were identified retrospectively. Landmark 12-week Kaplan-Meier analyses and log-rank tests were used to evaluate associations between discontinuation of induction therapy on overall survival and time to treatment failure (TTF). Multivariable analysis of factors influencing overall survival and TTF was undertaken. RESULTS: Among 95 patients, the median age was 62 years, 38.9% had Eastern Cooperative Oncology Group performance status ≥1 and 22.1% had brain metastases. The median follow-up for the whole cohort was 19.8 months by the reverse Kaplan-Meier method. Any grade and grade 3-4 irAE were noted in 78.9% and 44.2% of the cohort, respectively. 44.2% of patients completed induction immunotherapy, whereas 41.1% did not due to irAE. Twelve-week landmark overall survival and TTF were similar in patients who completed induction versus those who did not due to irAE. On multivariable analysis, any grade irAE (versus none) was associated with longer overall survival (hazard ratio = 0.35, 95% confidence interval 0.15-0.82, P = 0.02) and TTF (hazard ratio = 0.38, 95% confidence interval = 0.17-0.81, P = 0.01). Grade 3-4 irAE correlated with longer TTF (hazard ratio = 0.45, 95% confidence interval = 0.20-1.01, P = 0.05). CONCLUSION: In this population-based cohort, discontinuation of induction immunotherapy as a result of irAE did not adversely affect overall survival or TTF. irAE observed during ipilimumab and nivolumab induction were associated with improved survival outcomes.

Synthetic CT for single-fraction neoadjuvant partial breast irradiation on an MRI-linac.

A synthetic computed tomography (sCT) is required for daily plan optimization on an MRI-linac. Yet, only limited information is available on the accuracy of dose calculations on sCT for breast radiotherapy. This work aimed to (1) evaluate dosimetric accuracy of treatment plans for single-fraction neoadjuvant partial breast irradiation (PBI) on a 1.5 T MRI-linac calculated on a) bulk-density sCT mimicking the current MRI-linac workflow and b) deep learning-generated sCT, and (2) investigate the number of bulk-density levels required. For ten breast cancer patients we created three bulk-density sCTs of increasing complexity from the planning-CT, using bulk-density for: (1) body, lungs, and GTV (sCTBD1); (2) volumes for sCTBD1plus chest wall and ipsilateral breast (sCTBD2); (3) volumes for sCTBD2plus ribs (sCTBD3); and a deep learning-generated sCT (sCTDL) from a 1.5 T MRI in supine position. Single-fraction neoadjuvant PBI treatment plans for a 1.5 T MRI-linac were optimized on each sCT and recalculated on the planning-CT. Image evaluation was performed by assessing mean absolute error (MAE) and mean error (ME) in Hounsfield Units (HU) between the sCTs and the planning-CT. Dosimetric evaluation was performed by assessing dose differences, gamma pass rates, and dose-volume histogram (DVH) differences. The following results were obtained (median across patients for sCTBD1/sCTBD2/sCTBD3/sCTDLrespectively): MAE inside the body contour was 106/104/104/75 HU and ME was 8/9/6/28 HU, mean dose difference in the PTVGTVwas 0.15/0.00/0.00/-0.07 Gy, median gamma pass rate (2%/2 mm, 10% dose threshold) was 98.9/98.9/98.7/99.4%, and differences in DVH parameters were well below 2% for all structures except for the skin in the sCTDL. Accurate dose calculations for single-fraction neoadjuvant PBI on an MRI-linac could be performed on both bulk-density and deep learning sCT, facilitating further implementation of MRI-guided radiotherapy for breast cancer. Balancing simplicity and accuracy, sCTBD2showed the optimal number of bulk-density levels for a bulk-density approach.

A formalism for reference dosimetry in photon beams in the presence of a magnetic field.

A generic formalism is proposed for reference dosimetry in the presence of a magnetic field. Besides the regular correction factors from the conventional reference dosimetry formalisms, two factors are used to take into account magnetic field effects: (1) a dose conversion factor to correct for the change in local dose distribution and (2) a correction of the reading of the dosimeter used for the reference dosimetry measurements. The formalism was applied to the Elekta MRI-Linac, for which the 1.5 T magnetic field is orthogonal to the 7 MV photon beam. For this setup at reference conditions it was shown that the dose decreases with increasing magnetic field strength. The reduction in local dose for a 1.5 T transverse field, compared to no field is 0.51% ± 0.03% at the reference point of 10 cm depth. The effect of the magnetic field on the reading of the dosimeter was measured for two waterproof ionization chambers types (PTW 30013 and IBA FC65-G) before and after multiple ramp-up and ramp-downs of the magnetic field. The chambers were aligned perpendicular and parallel to the magnetic field. The corrections of the readings of the perpendicularly aligned chambers were 0.967 ± 0.002 and 0.957 ± 0.002 for respectively the PTW and IBA ionization chambers. In the parallel alignment the corrections were small; 0.997 ± 0.001 and 1.002 ± 0.003 for the PTW and IBA chamber respectively. The change in reading due to the magnetic field can be measured by individual departments. The proposed formalism can be used to determine the correction factors needed to establish the absorbed dose in a magnetic field. It requires Monte Carlo simulations of the local dose and measurements of the response of the dosimeter. The formalism was successfully implemented for the MRI-Linac and is applicable for other field strengths and geometries.

Spiraling contaminant electrons increase doses to surfaces outside the photon beam of an MRI-linac with a perpendicular magnetic field.

The transverse magnetic field of an MRI-linac sweeps contaminant electrons away from the radiation beam. Films oriented perpendicular to the magnetic field and 5 cm from the radiation beam edge show a projection of the divergent beam, indicating that contaminant electrons spiral along magnetic field lines and deposit dose on surfaces outside the primary beam perpendicular to the magnetic field. These spiraling contaminant electrons (SCE) could increase skin doses to protruding regions of the patient along the cranio-caudal axis. This study investigated doses from SCE for an MRI-linac comprising a 7 MV linac and a 1.5 T MRI scanner. Surface doses to films perpendicular to the magnetic field and 5 cm from the radiation beam edge showed increased dose within the projection of the primary beam, whereas films parallel to the magnetic field and 5 cm from the beam edge showed no region of increased dose. However, the dose from contaminant electrons is absorbed within a few millimeters. For large fields, the SCE dose is within the same order of magnitude as doses from scattered and leakage photons. Doses for both SCE and scattered photons decrease rapidly with decreasing beam size and increasing distance from the beam edge.

Beam characterisation of the 1.5 T MRI-linac.

As a prerequisite for clinical treatments it was necessary to characterize the Elekta 1.5 T MRI-linac 7 MV FFF radiation beam. Following acceptance testing, beam characterization data were acquired with Semiflex 3D (PTW 31021), microDiamond (PTW 60019), and Farmer-type (PTW 30013 and IBA FC65-G) detectors in an Elekta 3D scanning water phantom and a PTW 1D water phantom. EBT3 Gafchromic film and ion chamber measurements in a buildup cap were also used. Special consideration was given to scan offsets, detector effective points of measurement and avoiding air gaps. Machine performance has been verified and the system satisfied the relevant beam requirements of IEC60976. Beam data were acquired for field sizes between 1 × 1 and 57 × 22 cm2. New techniques were developed to measure percentage depth dose (PDD) curves including the electron return effect at beam exit, which exhibits an electron-type practical range of 1.2 ± 0.1 cm. The Lorentz force acting on the secondary charged particles creates an asymmetry in the crossline profiles with an average shift of +0.24 cm. For a 10 × 10 cm2 beam, scatter from the cryostat contributes 1% of the dose at isocentre. This affects the relative output factors, scatter factors and beam profiles, both in-field and out-of-field. The average 20%-80% penumbral width measured for small fields with a microDiamond detector at 10 cm depth is 0.50 cm. MRI-linac penumbral widths are very similar to that of the Elekta Agility linac MLC, as is the near-surface dose PDD(0.2 cm) = 57%. The entrance surface dose is ∼36% of Dmax. Cryostat transmission is quantified for inclusion within the treatment planning system. As a result, the 1.5 T MRI-linac 7 MV FFF beam has been characterised for the first time and is suitable for clinical use. This was a key step towards the first clinical treatments with the MRI-linac, which were delivered at University Medical Center Utrecht in May 2017 (Raaymakers et al 2017 Phys. Med. Biol. 62 L41-50).

First patients treated with a 1.5 T MRI-Linac: clinical proof of concept of a high-precision, high-field MRI guided radiotherapy treatment.

The integration of 1.5 T MRI functionality with a radiotherapy linear accelerator (linac) has been pursued since 1999 by the UMC Utrecht in close collaboration with Elekta and Philips. The idea behind this integrated device is to offer unrivalled, online and real-time, soft-tissue visualization of the tumour and the surroundings for more precise radiation delivery. The proof of concept of this device was given in 2009 by demonstrating simultaneous irradiation and MR imaging on phantoms, since then the device has been further developed and commercialized by Elekta. The aim of this work is to demonstrate the clinical feasibility of online, high-precision, high-field MRI guidance of radiotherapy using the first clinical prototype MRI-Linac. Four patients with lumbar spine bone metastases were treated with a 3 or 5 beam step-and-shoot IMRT plan. The IMRT plan was created while the patient was on the treatment table and based on the online 1.5 T MR images; pre-treatment CT was deformably registered to the online MRI to obtain Hounsfield values. Bone metastases were chosen as the first site as these tumors can be clearly visualized on MRI and the surrounding spine bone can be detected on the integrated portal imager. This way the portal images served as an independent verification of the MRI based guidance to quantify the geometric precision of radiation delivery. Dosimetric accuracy was assessed post-treatment from phantom measurements with an ionization chamber and film. Absolute doses were found to be highly accurate, with deviations ranging from 0.0% to 1.7% in the isocenter. The geometrical, MRI based targeting as confirmed using portal images was better than 0.5 mm, ranging from 0.2 mm to 0.4 mm. In conclusion, high precision, high-field, 1.5 T MRI guided radiotherapy is clinically feasible.

Consequences of air around an ionization chamber: Are existing solid phantoms suitable for reference dosimetry on an MR-linac?

PURPOSE: A protocol for reference dosimetry for the MR-linac is under development. The 1.5 T magnetic field changes the mean path length of electrons in an air-filled ionization chamber but has little effect on the electron trajectories in a surrounding phantom. It is therefore necessary to correct the response of an ionization chamber for the influence of the magnetic field. Solid phantoms are used for dosimetry measurements on the MR-linac, but air is present between the chamber wall and phantom insert. This study aimed to determine if this air influences the ion chamber measurements on the MR-linac. The absolute response of the chamber and reproducibility of dosimetry measurements were assessed on an MR-linac in solid and water phantoms. The sensitivity of the chamber response to the distribution of air around the chamber was also investigated. METHODS: Measurements were performed on an MR-linac and replicated on a conventional linac for five chambers. The response of three waterproof chambers was measured with air and with water between the chamber and the insert to measure the influence of the air volume on absolute chamber response. The distribution of air around the chamber was varied indirectly by rotating each chamber about the longitudinal chamber axis in a solid phantom and a water phantom (waterproof chambers only) and measuring the angular dependence of the chamber response, and varied directly by displacing the chamber in the phantom insert using a paper shim positioned at different orientations between the chamber casing and the insert. RESULTS: The responses of the three waterproof chambers measured on the MR-linac were 0.7%-1.2% higher with water than air in the chamber insert. The responses of the chambers on the conventional linac changed by less than 0.3% when air in the insert was replaced with water. The angular dependence of the chambers ranged from 0.6% to 1.9% in the solid phantom on the MR-linac but was less than 0.5% in water on the MR-linac and less than 0.3% in the solid phantom on the conventional linac. Inserting a shim around the chamber induced changes of the chamber response in a magnetic field of up to 2.2%, but the change in chamber response on the conventional linac was less than 0.3%. CONCLUSIONS: The interaction between the magnetic field and secondary electrons in the air around the chamber reduces the charge collected from 0.7% to 1.2%. The large angular dependence of ion chambers measured in the plastic phantom in a magnetic field appears to arise from a change of air distribution as the chamber is moved within the insert, rather than an intrinsic isotropy of the chamber sensitivity to radiation. It is recommended that reference dosimetry measurements on the MR-linac can be performed only in water, rather than in existing plastic phantoms.

Investment in attending to cues and the evolution of amplifiers.

Signals and cues are extensively used in social interactions across diverse communication systems. Here, we extend an existing theoretical framework to explore investment by emitters and perceivers in the fidelity with which cues and signals associated with the former are detected by the latter. Traits of the emitter that improve cue or signal fidelity without adding information are termed 'amplifiers'. We assume that each party can invest in improving fidelity but that it is increasingly costly the more fidelity is improved. Our model predicts that evolution of amplifier traits of a pre-existing cue occurs over a broader range of circumstances than evolution of signalling in situations where the emitter offered no pre-existing cue to the perceiver. It further predicts that the greater the intrinsic informational value of a cue, the more likely it is that the perceiver (and not the emitter) will invest in the fidelity of detecting that cue. A consequence of this predicted asymmetry is that true communication with reciprocal adaptations in emitters and perceivers to improve signal fidelity is likely to occur predominantly for traits of intermediate reliability. The corollary is that uncertainty of the perceiver will then be a key feature of communication. Uncertainty can arise because perceivers misinterpret signals or do not perceive them correctly, but here we argue that uncertainty is more fundamentally at the root of communication because traits that are intrinsically highly informative will induce only the perceiver and not the emitter to invest in improved fidelity of perception of that trait.

Anaphylaxis and ethnicity: higher incidence in British South Asians.

BACKGROUND: The incidence of anaphylaxis in South Asians (Indian, Pakistani and Bangladeshi ethnicity) is unknown. Birmingham is a British city with a disproportionately large population of South Asians (22.5%) compared with the rest of the UK (4.9%). The main aims of this study were to determine the incidence and severity of anaphylaxis in this population and to investigate the differences between the South Asian and White populations. METHODS: A retrospective electronic search of emergency department attendances at three hospitals in Birmingham during 2012 was carried out. Wide search terms were used, medical notes were scrutinized, and the World Allergy Organization diagnostic criteria for anaphylaxis were applied. Patients' age, sex, ethnicity and home postal code were collected, reactions were graded by severity, and other relevant details including specialist assessment were extracted. Multivariate analysis was undertaken using 2011 UK census data. RESULTS: Age-, sex- and ethnicity-standardized incidence rate of anaphylaxis was 34.5 per 100 000 person-years. Multivariate logistic regression which controlled for the confounders of age, sex and level of socioeconomic deprivation showed that incidence was higher in the South Asian population (OR 1.48, P = 0.005). Incidence rate in the South Asian population was 58.3 cases per 100 000 person-years compared to 31.5 in the White population. South Asian children were more likely to present with severe anaphylaxis (OR 5.31, P = 0.002). CONCLUSIONS: Incidence of anaphylaxis is significantly higher in British South Asians compared to the white population. British South Asian children are at a greater risk of severe anaphylaxis than White children.

Sub-Nyquist field trial using time frequency packed DP-QPSK super-channel within fixed ITU-T grid.

Sub-Nyquist time frequency packing technique was demonstrated for the first time in a super-channel field trial transmission over long-haul distances. The technique allows a limited spectral occupancy even with low order modulation formats. The transmission was successfully performed on a deployed Australian link between Sydney and Melbourne which included 995 km of uncompensated SMF with coexistent traffic. 40 and 100 Gb/s co-propagating channels were transmitted together with the super-channel in a 50 GHz ITU-T grid without additional penalty. The super-channel consisted of eight sub-channels with low-level modulation format, i.e. DP-QPSK, guaranteeing better OSNR robustness and reduced complexity with respect to higher order formats. At the receiver side, coherent detection was used together with iterative maximum-a-posteriori (MAP) detection and decoding. A 975 Gb/s DP-QPSK super-channel was successfully transmitted between Sydney and Melbourne within four 50GHz WSS channels (200 GHz). A maximum potential SE of 5.58 bit/s/Hz was achieved with an OSNR = 15.8 dB, comparable to the OSNR of the installed 100 Gb/s channels. The system reliability was proven through long term measurements. In addition, by closing the link in a loop back configuration, a potential SE∙d product of 9254 bit/s/Hz·km was achieved.

Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe.

INTRODUCTION: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management. METHODS: Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software. RESULTS: Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects. CONCLUSION: The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.

Linking signal fidelity and the efficiency costs of communication.

The handicap principle has been the overarching framework to explain the evolution and maintenance of communication. Yet, it is becoming apparent that strategic costs of signalling are not the only mechanism maintaining signal honesty. Rather, the fidelity of detecting signals can itself be strongly selected. Specifically, we argue that the fidelity of many signals will be constrained by the investment in signal generation and reception by the signaller and perceiver, respectively. Here, we model how investments in signal fidelity influence the emergence and stability of communication using a simple theoretical framework. The predictions of the model indicate that high-cost communication can be stable whereas low-cost intermediates are generally selected against. This dichotomy suggests that the most parsimonious route to the evolution of communication is for initial investment in communicative traits to be driven by noncommunicative functions. Such cues can appeal to pre-existing perceptual biases and thereby stimulate signal evolution. We predict that signal evolution will vary between systems in ways that can be linked to the economics of communication to the two parties involved.

Toxic shock syndrome surveillance in UK children.

BACKGROUND: Toxic shock syndrome (TSS) is an acute toxin-mediated illness caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes. There is no recent data regarding incidence, management and mortality of TSS in UK children. METHODS: Consultants from paediatric and burns units in the UK and Ireland, reported cases of TSS seen between November 2008 and December 2009, via the British Paediatric Surveillance Unit. Respondents were sent questionnaires requesting detailed information about TSS cases. Established criteria were used to divide cases into staphylococcal or streptococcal TSS. RESULTS: Forty-nine cases were identified overall; 29 cases of streptococcal TSS (18 confirmed and 11 probable) and 20 cases of staphylococcal TSS (15 confirmed and 5 probable). The incidence of TSS children in the UK & the Republic of Ireland was calculated to be 0.38 per 100 000 children. Children with staphylococcal TSS were older than those with streptococcal TSS (9.5 vs 3.8 years; p<0.003). Paediatric intensive care facilities were used for 78% of cases (invasive ventilatory support 69%; inotropic support 67%; haemofiltration 12%). Agents with antitoxin effects were underused; clindamycin 67%, intravenous immunoglobulin (IVIG) 20%, fresh frozen plasma 40%. There were eight deaths, all in the streptococcal group (28% of streptococcal cases)-none were given IVIG. CONCLUSIONS: Streptococcal TSS was as frequent as staphylococcal TSS, contrasting with previous literature. Children with streptococcal TSS had a higher mortality than those with staphylococcal TSS (28% vs 0%; p<0.05). Recommended immunomodulatory agents (IVIG and clindamycin) were underused. This study highlights the need for a guideline to improve management of TSS in children.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012.

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

A UK national audit of hereditary and acquired angioedema.

Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life-threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.

Immune deficiencies in children: an overview.

Primary immune deficiencies (PIDs) are disorders of the immune system that result in increased susceptibility to infectious disease, autoimmunity and malignancy. They are challenging to paediatricians as they can present anytime from birth to adolescence with a wide variety of signs and symptoms. It is important to diagnose PIDs promptly, especially more severe forms to prevent significant morbidity and mortality. However, significant challenges exist in deciding which children to investigate and when. We aim to give a basic understanding of the human immune system, the different presentations in a child that should alert a paediatrician about the possibility of PID and the possible underlying diagnosis. Additionally, we have developed a framework for a stepwise approach to investigating these children.