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

Event segmentation and emotional memory updating

Study of event segmentation's influence on emotional memory updating via hybrid fear conditioning / episodic memory experiments. An extension of prior work(Laing & Dunsmoor, 2025, JoCN: 'Event Segmentation Promotes the Reorganization of Emotional Memory'

Male Escorting, Safety & National Ugly Mugs: Queering Policy & Practice on the Reporting of Crimes Against Sex Workers

Men who sell sex to men are largely invisible in sex work research and policy discourse (Whowell and Gaffney, 2009; Whowell, 2010). Violence against sex workers is considered to be a gendered act, with men constructed as hyper-masculine pimps, clients or traffickers. Rarely are they considered sex workers or vulnerable to crimes being committed against them (Gaffney, 2007). This chapter draws on case studies and monitoring data from the National Ugly Mugs (NUM) scheme (a national reporting mechanism for crimes committed against sex workers), in order to highlight the range of incidents that male sex workers encounter and the barriers they face to reporting crimes. It argues that positioning sex workers and their performed sexual encounters within a queer conceptual framework is necessary in the context of progressive policy and practice. Exploring the experiences of male sex workers offers a more nuanced understanding of sex workers’ experiences of work-related crimes and sex work, more broadly; laying bare the flaws in radical feminist analyses, which present the extremity of simplistic ideological theory (Weitzer, 2005). Such theories have heavily influenced policy in recent decades, drawing attention away from the lived realities of male sex workers and marginalising their experiences as victims of crime. NUM has the potential to play a critical role in making visible the experiences of male sex workers and providing important learning about their support needs in relation to work-related crimes. The linking of NUM to formal police systems is a vital step towards recognition of the rights to protection under the law and justice for all sex workers who are victims of crime

Universal linear optics

Linear optics underpins tests of fundamental quantum mechanics and computer science, as well as quantum technologies. Here we experimentally demonstrate the longstanding goal of a single reprogrammable optical circuit that is sufficient to implement all possible linear optical protocols up to the size of that circuit. Our six-mode universal system consists of a cascade of 15 Mach-Zehnder interferometers with 30 thermo-optic phase shifters integrated into a single photonic chip that is electrically and optically interfaced for arbitrary setting of all phase shifters, input of up to six photons and their measurement with a 12 single-photon detector system. We programmed this system to implement heralded quantum logic and entangling gates, boson sampling with verification tests, and six-dimensional complex Hadamards. We implemented 100 Haar random unitaries with average fidelity 0.999 $\pm$ 0.001. Our system is capable of switching between these and any other linear optical protocol in seconds. These results point the way to applications across fundamental science and quantum technologies.Comment: Comments welcom

Durability of SARS-CoV-2-specific T cell responses at 12-months post-infection

AbstractBackgroundCharacterizing the longevity and quality of cellular immune responses to SARS-CoV-2 is critical to understanding immunologic approaches to protection against COVID-19. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Further analysis of the function, durability, and diversity of the cellular response long after natural infection, over a wider range of ages and disease phenotypes, is needed to further identify preventative and therapeutic interventions.MethodsWe identified participants in our multi-site longitudinal, prospective cohort study 12-months post SARS-CoV-2 infection representing a range of disease severity. We investigated the function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry. In parallel, the magnitude of SARS-CoV-2-specific antibodies was compared.ResultsSARS-CoV-2-specific antibodies and T cells were detected at 12-months post-infection. Severity of acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12-months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity.ConclusionsOur data show that SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12-months post-infection, with higher frequency noted in those who originally experienced severe disease.</jats:sec

Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19

AbstractThe associations between clinical phenotypes of coronavirus disease 2019 (COVID-19) and the host inflammatory response during the transition from peak illness to convalescence are not yet well understood. Blood plasma samples were collected from 129 adult SARS-CoV-2 positive inpatient and outpatient participants between April 2020 and January 2021, in a multi-center prospective cohort study at 8 military hospitals across the United States. Plasma inflammatory protein biomarkers were measured in samples from 15 to 28 days post symptom onset. Topological Data Analysis (TDA) was used to identify patterns of inflammation, and associations with peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated using logistic regression. The study population (n = 129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct inflammatory biomarker clusters were identified and were associated with significant differences in peak disease severity (p &lt; 0.001), age (p &lt; 0.001), BMI (p &lt; 0.001), and CCI (p = 0.001). Host-biomarker profiles stratified a heterogeneous population of COVID-19 patients during the transition from peak illness to convalescence, and these distinct inflammatory patterns were associated with comorbid disease and severe illness due to COVID-19.</jats:p

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

BackgroundCausal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort.MethodsGS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants.ResultsWe successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19).ConclusionWe describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative