For electron beam reference dosimetry in radiotherapy, it is shown that by choosing the reference depth as dref = 0.6R(50)-0.1 cm, where R50 is the half-value depth in centimeters, the Spencer-Attix water-to-air stopping-power ratio at dref is given by (Llp)airw = 1.2534 - 0.1487 (R50)0.2144. This is derived from data for (Llp)airw obtained from realistic Monte Carlo simulations for 24 clinical beams. The rms deviation of this expression from the Monte Carlo calculations is 0.16%, with a maximum deviation of 0.26%. This approach fully takes into account the spectral differences between real electron beams of the same R50 and allows an absorbed-dose calibration at a standards laboratory to be easily and accurately transferred to a reference clinical beam. Using a single parameter to specify (Llp)airw, rather than the two parameters (R50 and depth) needed when the reference depth is chosen as the depth of dose maximum, has the potential to greatly simplify electron beam dosimetry protocols and allows the use of a similar formalism for photon and electron beam dosimetry. For use in converting a depth-ionization curve into a depth-dose curve, a somewhat less accurate but general expression for (Llp)w(air) as a function of R50 and depth is presented.

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals’ fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161∗). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.

The NACP electron chamber is one of three parallel-plate chambers recommended for use in the UK. Measurements with this chamber type have indicated a problem in determining the recombination correction. This is due to a variation of the ionization current I with polarizing voltage V which deviates from the accepted Boag theory. It is shown that there is a chamber-dependent threshold voltage below which the NACP chamber follows the Boag theory. Above this voltage the chamber should be used with caution, although it is still possible to correct for the dependence of the chamber response on the dose per pulse. The existence of such deviations from theory demonstrates the usefulness of the 1/I against 1/V plot and the limitations of the Boag two-voltage analysis. Values for the initial recombination and the coefficient of general recombination are measured for several NACP chambers. It is shown that from these one can derive a value for the effective plate separation and the collector radius of each chamber. Differences in the behaviour of NACP chambers manufactured by Scanditronix and Dosetek are discussed and the implications of free-electron collection are considered.

Substantial changes in ion chamber perturbation correction factors in (60)Co γ-rays, suggested by recent Monte Carlo (MC) calculations, would cause a decrease of about 1.5% in the reference dosimetry of all types of charged particles (electrons, protons and heavier ions) based on calculated kQ values. It has gone largely unnoticed that the ratio of calibration coefficients ND, w, Co60 and NK, air, Co60 yields an experimental value of Fch, Co60 = (sw-air pch)Co60 through ND, air, Co60. Coefficients provided by the IAEA and traceable to the BIPM for 91 NE-2571 chambers result in an average Fch, Co60 which is compared with published (and new) MC simulations and with the value in IAEA TRS-398. It is shown that TRS-398 agrees within 0.12% with the experimental Fch, Co60. The 1.5% difference resulting from MC calculations (1.1% for the new simulations) cannot be justified using current fundamental data and BIPM standards if consistency in the entire dosimetry chain is sought. For photons, MC kQ factors are compared with TRS-398. Using the same uncertainty for Wair, the two sets of data overlap considerably. Experimental kQ values from standards laboratories lie between the two sets of calculated values, showing no preference for one set over the other. Observed chamber-to-chamber differences, that include the effect of waterproof sleeves (also seen for (60)Co), justify the recommendation in TRS-398 for kQ values specifically measured for the user chamber. Current developments on I-values for the stopping powers of water and graphite are presented. A weighted average Iwater = 78 ± 2 eV is obtained from published experimental and DRF-based values; this would decrease sw-air for all types of radiotherapy beams between 0.3% and 0.6%, and would consequently decrease the MC derived Fch, Co60. The implications of a recent proposal for Igraphite = 81 eV are analysed, resulting in a potential decrease of 0.7% in NK, air, Co60 which would raise the experimental Fch, Co60; this would result in an increase of about 0.8% in the current TRS-398 value when referred to the BIPM standards. MC derived Fch, Co60 using new stopping powers would then agree at a level of 0.1% with the experimental value, confirming the need for consistency in the dosimetry chain data. Should world average standards be used as reference, the figures would become +0.4% for TRS-398 and -0.3% for the MC calculation. Fch, Q calculated for megavoltage photons using new stopping powers would decrease by between 0.2% and 0.5%. When they enter as a ratios in kQ, differences with MC values based on current key data would be within 0.2% but their discrepancy with kQ experimental photon values remains unresolved. For protons the new data would require an increase in Wair, Q of about 0.6%, as this is inferred from a combination of calorimetry and ionometry. This consistent scenario would leave unchanged the current TRS-398 kQ (NE-2571) data for protons, as well as for ions heavier than protons unless new independent Wair, Q values become available. Also in these advance...

The IAEA is currently coordinating a multi-year project to update the TRS-398 Code of Practice for the dosimetry of external beam radiotherapy based on standards of absorbed dose to water. One major aspect of the project is the determination of new beam quality correction factors, k Q , for megavoltage photon beams consistent with developments in radiotherapy dosimetry and technology since the publication of TRS-398 in 2000. Specifically, all values must be based on, or consistent with, the key data of ICRU Report 90.Data sets obtained from Monte Carlo (MC) calculations by advanced users and measurements at primary standards laboratories have been compiled for 23 cylindrical ionization chamber types, consisting of 725 MC-calculated and 179 experimental data points. These have been used to derive consensus k Q values as a function of the beam quality index TPR 20,10 with a combined standard uncertainty of 0.6%. Mean values of MC-derived chamber-specific f ch factors for cylindrical and plane-parallel chamber types in 60 Co beams have also been obtained with an estimated uncertainty of 0.4%.

Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation.

A consistent formalism is presented using Monte Carlo calculations to determine the reference air kerma from the measured energy deposition in a primary-standard cavity ionization chamber. A global approach avoiding the use of cavity ionization theory is discussed and its limitations shown in relation to the use of the recommended value for W. The role of charged-particle equilibrium is outlined and the consequent requirements placed on the calculations are detailed. Values for correction factors are presented for the BIPM air-kerma standard for 60Co, making use of the Monte Carlo code PENELOPE, a detailed geometrical model of the BIPM 60Co source and event-by-event electron transport. While the wall correction factor k(wall) = 1.0012(2) is somewhat lower than the existing value, the axial non-uniformity correction k(an) = 1.0027(3) is significantly higher. The use of a point source in the evaluation of k(an) is discussed. A comparison is made of the calculated dose ratio with the Bragg-Gray and Spencer-Attix stopping-power ratios, the results indicating a preference for the Bragg-Gray approach in this particular case. A change to the recommended value for W of up to 2 parts in 10(3) is discussed. The uncertainties arising from the geometrical models, the use of phase-space files, the radiation transport algorithms and the underlying radiation interaction coefficients are estimated.

A systematic analysis of the available data has been carried out for mass energy-absorption coefficients and their ratios for air, graphite and water for photon energies between 1 keV and 2 MeV, using representative kilovoltage x-ray spectra for mammography and diagnostic radiology below 100 kV, and for ¹⁹²Ir and ⁶⁰Co gamma-ray spectra. The aim of this work was to establish 'an envelope of uncertainty' based on the spread of the available data. Type A uncertainties were determined from the results of Monte Carlo (MC) calculations with the PENELOPE and EGSnrc systems, yielding mean values for µ(en)/ρ with a given statistical standard uncertainty. Type B estimates were based on two groupings. The first grouping consisted of MC calculations based on a similar implementation but using different data and/or approximations. The second grouping was formed by various datasets, obtained by different authors or methods using the same or different basic data, and with different implementations (analytical, MC-based, or a combination of the two); these datasets were the compilations of NIST, Hubbell, Johns-Cunningham, Attix and Higgins, plus MC calculations with PENELOPE and EGSnrc. The combined standard uncertainty, u(c), for the µ(en)/ρ values for the mammography x-ray spectra is 2.5%, decreasing gradually to 1.6% for kilovoltage x-ray spectra up to 100 kV. For ⁶⁰Co and ¹⁹²Ir, u(c) is approximately 0.1%. The Type B uncertainty analysis for the ratios of µ(en)/ρ values includes four methods of analysis and concludes that for the present data the assumption that the data interval represents 95% confidence limits is a good compromise. For the mammography x-ray spectra, the combined standard uncertainties of (µ(en)/ρ)(graphite,air) and (µ(en)/ρ)(graphite,water) are 1.5%, and 0.5% for (µ(en)/ρ)(water,air), decreasing gradually down to u(c) = 0.1% for the three µ(en)/ρ ratios for the gamma-ray spectra. The present estimates are shown to coincide well with those of Hubbell (1977 Rad. Res. 70 58-81), except for the lowest energy range (radiodiagnostic) where it is concluded that current databases and their systematic analysis represent an improvement over the older Hubbell estimations. The results for (µ(en)/ρ)(graphite,air) for the gamma-ray dosimetry range are moderately higher than those of Seltzer and Bergstrom (2005 private communication).