Assessing Simulations of Imperial Dynamics and Conflict in the Ancient World

The development of models to capture large-scale dynamics in human history is one of the core contributions of cliodynamics. Most often, these models are assessed by their predictive capability on some macro-scale and aggregated measure and compared to manually curated historical data. In this report, we consider the model from Turchin et al. (2013), where the evaluation is done on the prediction of "imperial density": the relative frequency with which a geographical area belonged to large-scale polities over a certain time window. We implement the model and release both code and data for reproducibility. We then assess its behaviour against three historical data sets: the relative size of simulated polities vs historical ones; the spatial correlation of simulated imperial density with historical population density; the spatial correlation of simulated conflict vs historical conflict. At the global level, we show good agreement with population density ($R^2 < 0.75$), and some agreement with historical conflict in Europe ($R^2 < 0.42$). The model instead fails to reproduce the historical shape of individual polities. Finally, we tweak the model to behave greedily by having polities preferentially attacking weaker neighbours. Results significantly degrade, suggesting that random attacks are a key trait of the original model. We conclude by proposing a way forward by matching the probabilistic imperial strength from simulations to inferred networked communities from real settlement data

SATRE: Standardised Architecture for Trusted Research Environments

The SATRE DARE UK-funded Driver Project was challenged to create a trusted research environment (TRE) architecture supporting the research community's need to have suitable data analytics and research environments for working with sensitive data. The project developed an inclusive and transparent way of working to ensure that what was created was representative of the TRE community in the UK. We have created, for the first time, an open specification for TRE operators by which to evaluate themselves against a set of capabilities. It is a thorough specification, perhaps definition, for TREs informed not only by the experience of the project team who have been running a TRE and supporting sensitive data projects for a combined 15 years but also the expansive knowledge of the wider UK research community. The public has also been involved throughout the development of the specification to ensure their voices are heard and reflected in the specification. The specification has been informed through one survey completed by 105 individuals representing approximately 60 organisations, 14 Collaboration Cafés with up to 75 participants, 26 individuals contributing directly, 44 issues raised and six public engagement sessions online and in-person. Despite the breadth and diversity of the individuals included, we have been able to create a single specification encompassing four architectural principles, four pillars, 29 capabilities and 160 statements. The 75 mandatory statements are what is considered the minimum required to be a SATRE-compliant TRE. Now, with a stable version 1.0 release, the specification is ready for use by the UK TRE community. We are and will continue to work with all organisations to evaluate themselves against the specification and also identify what works and what doesn't, which will be captured in future versions of the specification. The specification has been developed with the long-term in mind and can be a basis for a common understanding between operators, data controllers, accreditors, researchers, industry and government organisations for how TREs can federate and interoperate better.This work was funded by UK Research &amp; Innovation [Grant Number MC_PC_23008] as part of Phase 1 of the DARE UK (Data and Analytics Research Environments UK) programme, delivered in partnership with Health Data Research UK (HDR UK) and Administrative Data Research UK (ADR UK)

Insights into Land Plant Evolution Garnered from the Marchantia polymorpha Genome.

The evolution of land flora transformed the terrestrial environment. Land plants evolved from an ancestral charophycean alga from which they inherited developmental, biochemical, and cell biological attributes. Additional biochemical and physiological adaptations to land, and a life cycle with an alternation between multicellular haploid and diploid generations that facilitated efficient dispersal of desiccation tolerant spores, evolved in the ancestral land plant. We analyzed the genome of the liverwort Marchantia polymorpha, a member of a basal land plant lineage. Relative to charophycean algae, land plant genomes are characterized by genes encoding novel biochemical pathways, new phytohormone signaling pathways (notably auxin), expanded repertoires of signaling pathways, and increased diversity in some transcription factor families. Compared with other sequenced land plants, M. polymorpha exhibits low genetic redundancy in most regulatory pathways, with this portion of its genome resembling that predicted for the ancestral land plant. PAPERCLIP

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial

Background: Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. Methods: Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. Results: Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). Interpretation: The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer. Funding: Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council