Sex‐Specific Variability in the Immune System across Life‐History Stages.

Organisms theoretically manage their immune systems optimally across their life spans to maximize fitness. However, we lack information on (1) how the immune system is managed across life‐history stages, (2) whether the sexes manage immunity differentially, and (3) whether immunity is repeatable within an individual. We present a within‐individual, repeated‐measures experiment examining life‐history stage variation in the inflammatory immune response in the zebra finch (Taeniopygia guttata). In juveniles, age‐dependent variation in immune response differed in a sex‐ and context‐specific manner, resulting in no repeatability across stages. In adults, females displayed little stage‐dependent variation in immune response when laying while receiving a high‐quality (HQ) diet; however, laying while receiving a low‐quality (LQ) diet significantly reduced both immune responses and reproductive outputs in a manner consistent with a facultative (resource‐driven) effect of reproduction on immunity. Moreover, a reduced immune response in females who were raising offspring while receiving an HQ diet suggests a residual effect of the energetic costs of reproduction. Conversely, adult males displayed no variation in immune responses across stages, with high repeatability from the nonbreeding stage to the egg‐laying stage, regardless of diet quality (HQ diet, $r=0.51$; LQ diet, $r=0.42$). Females displayed high repeatability when laying while receiving the HQ diet ($r=0.53$); however, repeatability disappeared when individuals received the LQ diet. High‐response females receiving the HQ diet had greater immune flexibility than did low‐response females who were laying while receiving the LQ diet. Data are consistent with immunity being a highly plastic trait that is sex‐specifically modulated in a context‐dependent manner and suggest that immunity at one stage may provide limited information about immunity at future stages

X-Ray fluorescence analysis of feldspars and silicate glass: effects of melting time on fused bead consistency and volatilisation

Reproducible preparation of lithium tetraborate fused beads for XRF analysis of glass and mineral samples is of paramount importance for analytical repeatability. However, as with all glass melting processes, losses due to volatilization must be taken into account and their effects are not negligible. Here the effects of fused bead melting time have been studied for four Certified Reference Materials (CRM’s-three feldspars, one silicate glass), in terms of their effects on analytical variability and volatilization losses arising from fused bead preparation. At melting temperatures of 1065 °C, and for feldspar samples, fused bead melting times shorter than approximately 25 minutes generally gave rise to greater deviation of XRF-analyzed composition from certified composition. This variation might be due to incomplete fusion and / or fused bead inhomogeneity but further research is needed. In contrast, the shortest fused bead melting time for the silicate glass CRM gave an XRF-analyzed composition closer to the certified values than longer melting times. This may suggest a faster rate of glass-in-glass dissolution and homogenization during fused bead preparation. For all samples, longer melting times gave rise to greater volatilization losses (including sulphates and halides) during fusion. This was demonstrated by a linear relationship between SO3 mass loss and time1/2, as predicted by a simple diffusion-based model. Iodine volatilization displays a more complex relationship, suggestive of diffusion plus additional mechanisms. This conclusion may have implications for vitrification of iodine-bearing radioactive wastes. Our research demonstrates that the nature of the sample material impacts on the most appropriate fusion times. For feldspars no less than ~25 min and no more than ~60 min of fusion at 1065 °C, using Li2B4O7 as the fusion medium and in the context of feldspar samples and the automatic fusion equipment used here, strikes an acceptable (albeit non-ideal) balance between the competing factors of fused bead quality, analytical consistency and mitigating volatilization losses. Conversely, for the silicate glass sample, shorter fusion times of less than ~30 minutes under the same conditions provided more accurate analyses whilst limiting volatile losses

X-ray Fluorescence Analysis of Feldspars and Silicate Glass: Effects of Melting Time on Fused Bead Consistency and Volatilisation

Reproducible preparation of lithium tetraborate fused beads for XRF analysis of glass and mineral samples is of paramount importance for analytical repeatability. However, as with all glass melting processes, losses due to volatilisation must be taken into account and their effects are not negligible. Here the effects of fused bead melting time have been studied for four Certified Reference Materials (CRM’s: three feldspars, one silicate glass), in terms of their effects on analytical variability and volatilisation losses arising from fused bead preparation. At melting temperatures of 1065 °C, and for feldspar samples, fused bead melting times shorter than approximately 25 min generally gave rise to a greater deviation of the XRF-analysed composition from the certified composition. This variation might be due to incomplete fusion and/or fused bead inhomogeneity but further research is needed. In contrast, the shortest fused bead melting time for the silicate glass CRM gave an XRF-analysed composition closer to the certified values than longer melting times. This may suggest a faster rate of glass-in-glass dissolution and homogenization during fused bead preparation. For all samples, longer melting times gave rise to greater volatilisation losses (including sulphates and halides) during fusion. This was demonstrated by a linear relationship between SO3 mass loss and time1/2, as predicted by a simple diffusion-based model. Iodine volatilisation displays a more complex relationship, suggestive of diffusion plus additional mechanisms. This conclusion may have implications for vitrification of iodine-bearing radioactive wastes. Our research demonstrates that the nature of the sample material impacts on the most appropriate fusion times. For feldspars no less than ~25 min and no more than ~60 min of fusion at 1065 °C, using Li2B4O7 as the fusion medium and in the context of feldspar samples and the automatic fusion equipment used here, strikes an acceptable (albeit non-ideal) balance between the competing factors of fused bead quality, analytical consistency and mitigating volatilisation losses. Conversely, for the silicate glass sample, shorter fusion times of less than ~30 min under the same conditions provided more accurate analyses whilst limiting volatile losses

A pandemic treaty for equitable global access to medical countermeasures:seven recommendations for sharing intellectual property, know-how and technology Comment

The COVID-19 pandemic highlighted how current international laws and practices fail to ensure medical countermeasures (ie, vaccines, therapeutics, diagnostics and personal protective equipment) are equitably distributed in a global health crisis. In 2021, the 194 Member States of the World Health Organization agreed to begin negotiations towards an international instrument that would better position the world to prevent, respond and prepare for future pandemics (often called a ‘pandemic treaty’.) A pandemic treaty presents an opportunity to address these challenges in international law, and craft a better system, based on solidarity, for the global development and distribution of medical countermeasures. We recommend that a pandemic treaty ensures sufficient financing for biomedical research and development (R&D), creates conditions for licensing government-funded R&D, mandates technology transfer, shares intellectual property, data and knowledge needed for the production and supply of products, and streamlines regulatory standards and procedures to market medical countermeasures. We also recommend that a pandemic treaty ensures greater transparency and inclusive governance of these systems. The aim of these components in a pandemic treaty should be to craft a better collective response to global health threats, consistent with existing international law, political commitments and sound public health practice

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

West African drumming rhythms in contemporary piano music

The aim of “West African Drumming Rhythms in Contemporary Piano Music” was to create a coherent overall package containing a folio of original piano compositions informed by traditional West African drumming rhythms, a CD of their performances along with examples of the traditional rhythmic sources performed on traditional African instruments, as well as accompanying original scores at a publishable level. A total of eight pieces have been composed, seven of which feature literal transcriptions of traditional West African drumming rhythms. The eighth piece demonstrates compositional opportunities with free use of drum rhythms and scope for further exploration. All compositions have been analysed and have accompanying performance notes

Phosphate solubility and its effects on US radioactive waste glass properties

The Hanford Site in Washington State, USA is a decommissioned nuclear production site, home to 250 000 m3 of radioactive waste which is stored in 158 steel tanks, initially only for short term use and now subject to extensive and widespread corrosion problems. Numerous tanks are leaking radioactive ‘sludge’ containing a complex mixture of many elements of the periodic table. In an effort to clean up the waste, vitrification implementing a borosilicate glass composition was selected in 1989 as a means of safer disposal. However, previous research has identified that the final vitrified waste form may still be susceptible to leaching, leading to the potential release of radionuclides and other toxic components into groundwater in geological repositories. One potentially problematic component of the waste arises as a result of pre-processing: phosphorus compounds. Phosphorus pentoxide (P2O5) is poorly soluble in borosilicate glass systems, with concentrations >3.2 mol% (>4.5 wt%) potentially leading to phase separation that can affect melt viscosity and chemical durability. These are of particular importance because an overly viscous melt will be unpourable and may damage the melter if the increase in viscosity is due to the presence of crystallites and/or salt accumulation; and poor chemical durability could result in the leaching of radionuclides within geological repositories, ultimately resulting in groundwater contamination. Hence, it is important to establish the effects of different levels of P2O5 on the properties of radioactive waste borosilicate glasses. This research investigated the effects of doping and altering the P2O5 content on the structure and properties of borosilicate glass compositions based on Hanford high level waste (HLW), low level activity waste (LAW), and immobilised low level activity waste (ILAW). X-ray fluorescence (XRF) spectroscopy and Inductively Coupled Plasma Optical Emission spectroscopy (ICP-OES) were used to analyse the chemical composition. X-ray diffraction (XRD) was used for crystalline phase identification and to confirm the amorphous nature of the glasses, where crystalline phases were quantified using Rietveld analysis and visually imaged using scanning electron microscopy (SEM). Glass structure was analysed using Raman spectroscopy, 57Fe Mössbauer spectroscopy, X-ray absorption near edge structure (XANES) spectroscopy, and magic angle spinning nuclear magnetic resonance (MAS-NMR) spectroscopy. The rheological behaviour of melts was investigated using high temperature viscosity (HTV) measurements, whilst glass chemical durability was analysed using the 7-day product consistency test (PCT) method B, and the thermal properties were determined using differential thermal analysis (DTA) and dilatometry. The main findings were that simple sodium borosilicate glasses had a solubility limit of between 2.7 ± 0.02 and 4.0 ± 0.01 mol% P2O5. When glass compositions were further complicated with additions of other oxides to more accurately represent Hanford HLW and LAW glass waste forms, the solubility limits of P2O5 were lower: between 0.69 ± 0.03 and 1.19 ± 0.00 mol% P2O5 for the HLW glasses, and 1.86 ± 0.00 and 2.04 ± 0.02 mol% P2O5 for LAW glasses. When P2O5 was added to a ILAW simulant glass its solubility was >0.71 ± 0.03 mol%. When the solubility limit was exceeded in these glass systems, nucleation-type phase separation and crystallisation occurred, producing phosphate-based crystal phases. Whilst the additions of P2O5 did not seem to increase the solubility of other components, in particular sulphate (SO42-), it did lead to the suppression of crystallisation in the heat treated HLW glasses. The structural analysis of the simple sodium borosilicate glasses doped with P2O5 provided an insight into the effects of P2O5 whilst its behaviour could be inferred in more complicated glasses. P2O5 initially entered the borosilicate glass structure as ultraphosphate (Q3P) but changed to orthophosphate (Q0P), pyrophosphate (Q1P), and metaphosphate (Q2P) as a function of the P2O5 concentration, where the lack of change in the boron (3+) tetrahedral ion, boron (3+) trigonal ion ([3]B3+:[4]B3+) ratio with increasing P2O5 content suggested that the phosphorus (P5+) was potentially entering the [4]B sub-network, but where its oxygen (O2-) was supplied by the silicate network, causing the non-bridging oxygens (NBØs) on the silicon (Si4+) to transform into bridging oxygens (BØs) resulting in its re-polymerisation, as evidenced by the decrease in the Q3Si and increase in Q4Si units. These glass systems provided a guide to the maximum P2O5 contents that can be present in the vitrified waste to avoid any potentially undesirable effects of phase separation and / or crystallisation. Insights into the structural changes and crystallisation behaviour of these glass systems, caused by altering their compositions, can be used to help inform crystallisation discriminators (parameters determining crystallisation tolerances) used to limit the waste loading of glasses prepared from Hanford wastes with high P2O5 contents