Analysis of detector performance in a gigahertz clock rate quantum key distribution system

We present a detailed analysis of a gigahertz clock rate environmentally robust phase-encoded quantum key distribution (QKD) system utilizing several different single-photon detectors, including the first implementation of an experimental resonant cavity thin-junction silicon single-photon avalanche diode. The system operates at a wavelength of 850 nm using standard telecommunications optical fibre. A general-purpose theoretical model for the performance of QKD systems is presented with reference to these experimental results before predictions are made about realistic detector developments in this system. We discuss, with reference to the theoretical model, how detector operating parameters can be further optimized to maximize key exchange rates

Optimality of mutation and selection in germinal centers

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.Comment: 5 figures in main text, and 4 figures in Supplementary Informatio

Study protocol: national research partnership to improve primary health care performance and outcomes for Indigenous peoples

Background Strengthening primary health care is critical to reducing health inequity between Indigenous and non-Indigenous Australians. The Audit and Best practice for Chronic Disease Extension (ABCDE) project has facilitated the implementation of modern Continuous Quality Improvement (CQI) approaches in Indigenous community health care centres across Australia. The project demonstrated improvements in health centre systems, delivery of primary care services and in patient intermediate outcomes. It has also highlighted substantial variation in quality of care. Through a partnership between academic researchers, service providers and policy makers, we are now implementing a study which aims to 1) explore the factors associated with variation in clinical performance; 2) examine specific strategies that have been effective in improving primary care clinical performance; and 3) work with health service staff, management and policy makers to enhance the effective implementation of successful strategies. Methods/Design The study will be conducted in Indigenous community health centres from at least six States/Territories (Northern Territory, Western Australia, New South Wales, South Australia, Queensland and Victoria) over a five year period. A research hub will be established in each region to support collection and reporting of quantitative and qualitative clinical and health centre system performance data, to investigate factors affecting variation in quality of care and to facilitate effective translation of research evidence into policy and practice. The project is supported by a web-based information system, providing automated analysis and reporting of clinical care performance to health centre staff and management. Discussion By linking researchers directly to users of research (service providers, managers and policy makers), the partnership is well placed to generate new knowledge on effective strategies for improving the quality of primary health care and fostering effective and efficient exchange and use of data and information among service providers and policy makers to achieve evidence-based resource allocation, service planning, system development, and improvements of service delivery and Indigenous health outcomes.Ross Bailie, Damin Si, Cindy Shannon, James Semmens, Kevin Rowley, David J Scrimgeour, Tricia Nage, Ian Anderson, Christine Connors, Tarun Weeramanthri, Sandra Thompson, Robyn McDermott, Hugh Burke, Elizabeth Moore, Dallas Leon, Richard Weston, Haylene Grogan, Andrew Stanley and Karen Gardne

Genome-wide inference of regulatory networks in Streptomyces coelicolor

Background: The onset of antibiotics production in Streptomyces species is co-ordinated with differentiation events. An understanding of the genetic circuits that regulate these coupled biological phenomena is essential to discover and engineer the pharmacologically important natural products made by these species. The availability of genomic tools and access to a large warehouse of transcriptome data for the model organism, Streptomyces coelicolor, provides incentive to decipher the intricacies of the regulatory cascades and develop biologically meaningful hypotheses. Results: In this study, more than 500 samples of genome-wide temporal transcriptome data, comprising wild-type and more than 25 regulatory gene mutants of Streptomyces coelicolor probed across multiple stress and medium conditions, were investigated. Information based on transcript and functional similarity was used to update a previously-predicted whole-genome operon map and further applied to predict transcriptional networks constituting modules enriched in diverse functions such as secondary metabolism, and sigma factor. The predicted network displays a scale-free architecture with a small-world property observed in many biological networks. The networks were further investigated to identify functionally-relevant modules that exhibit functional coherence and a consensus motif in the promoter elements indicative of DNA-binding elements. Conclusions: Despite the enormous experimental as well as computational challenges, a systems approach for integrating diverse genome-scale datasets to elucidate complex regulatory networks is beginning to emerge. We present an integrated analysis of transcriptome data and genomic features to refine a whole-genome operon map and to construct regulatory networks at the cistron level in Streptomyces coelicolor. The functionally-relevant modules identified in this study pose as potential targets for further studies and verification.

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

DATA AND MATERIALS AVAILABILITY : The full dataset used in the final analyses (33) and associated code (34) are available at Dryad. A subset of the spatial coordinate datasets is available at Zenodo (35). Certain datasets of spatial coordinates will be available only through requests made to the authors due to conservation and Indigenous sovereignty concerns (see table S1 for more information on data use restrictions and contact information for data requests). These sensitive data will be made available upon request to qualified researchers for research purposes, provided that the data use will not threaten the study populations, such as by distribution or publication of the coordinates or detailed maps. Some datasets, such as those overseen by government agencies, have additional legal restrictions on data sharing, and researchers may need to formally apply for data access. Collaborations with data holders are generally encouraged, and in cases where data are held by Indigenous groups or institutions from regions that are under-represented in the global science community, collaboration may be required to ensure inclusion.COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals’ 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.The Radboud Excellence Initiative, the German Federal Ministry of Education and Research, the National Science Foundation, Serbian Ministry of Education, Science and Technological Development, Dutch Research Council NWO program “Advanced Instrumentation for Wildlife Protection”, Fondation Segré, RZSS, IPE, Greensboro Science Center, Houston Zoo, Jacksonville Zoo and Gardens, Nashville Zoo, Naples Zoo, Reid Park Zoo, Miller Park, WWF, ZCOG, Zoo Miami, Zoo Miami Foundation, Beauval Nature, Greenville Zoo, Riverbanks zoo and garden, SAC Zoo, La Passarelle Conservation, Parc Animalier d’Auvergne, Disney Conservation Fund, Fresno Chaffee zoo, Play for nature, North Florida Wildlife Center, Abilene Zoo, a Liber Ero Fellowship, the Fish and Wildlife Compensation Program, Habitat Conservation Trust Foundation, Teck Coal, and the Grand Teton Association. The collection of Norwegian moose data was funded by the Norwegian Environment Agency, the German Ministry of Education and Research via the SPACES II project ORYCS, the Wyoming Game and Fish Department, Wyoming Game and Fish Commission, Bureau of Land Management, Muley Fanatic Foundation (including Southwest, Kemmerer, Upper Green, and Blue Ridge Chapters), Boone and Crockett Club, Wyoming Wildlife and Natural Resources Trust, Knobloch Family Foundation, Wyoming Animal Damage Management Board, Wyoming Governor’s Big Game License Coalition, Bowhunters of Wyoming, Wyoming Outfitters and Guides Association, Pope and Young Club, US Forest Service, US Fish and Wildlife Service, the Rocky Mountain Elk Foundation, Wyoming Wild Sheep Foundation, Wild Sheep Foundation, Wyoming Wildlife/Livestock Disease Research Partnership, the US National Science Foundation [IOS-1656642 and IOS-1656527, the Spanish Ministry of Economy, Industry and Competitiveness, and by a GRUPIN research grant from the Regional Government of Asturias, Sigrid Rausing Trust, Batubay Özkan, Barbara Watkins, NSERC Discovery Grant, the Federal Aid in Wildlife Restoration act under Pittman-Robertson project, the State University of New York, College of Environmental Science and Forestry, the Ministry of Education, Youth and Sport of the Czech Republic, the Ministry of Agriculture of the Czech Republic, Rufford Foundation, an American Society of Mammalogists African Graduate Student Research Fund, the German Science Foundation, the Israeli Science Foundation, the BSF-NSF, the Ministry of Agriculture, Forestry and Food and Slovenian Research Agency (CRP V1-1626), the Aage V. Jensen Naturfond (project: Kronvildt - viden, værdier og værktøjer), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy, National Centre for Research and Development in Poland, the Slovenian Research Agency, the David Shepherd Wildlife Foundation, Disney Conservation Fund, Whitley Fund for Nature, Acton Family Giving, Zoo Basel, Columbus, Bioparc de Doué-la-Fontaine, Zoo Dresden, Zoo Idaho, Kolmården Zoo, Korkeasaari Zoo, La Passarelle, Zoo New England, Tierpark Berlin, Tulsa Zoo, the Ministry of Environment and Tourism, Government of Mongolia, the Mongolian Academy of Sciences, the Federal Aid in Wildlife Restoration act and the Illinois Department of Natural Resources, the National Science Foundation, Parks Canada, Natural Sciences and Engineering Research Council, Alberta Environment and Parks, Rocky Mountain Elk Foundation, Safari Club International and Alberta Conservation Association, the Consejo Nacional de Ciencias y Tecnología (CONACYT) of Paraguay, the Norwegian Environment Agency and the Swedish Environmental Protection Agency, EU funded Interreg SI-HR 410 Carnivora Dinarica project, Paklenica and Plitvice Lakes National Parks, UK Wolf Conservation Trust, EURONATUR and Bernd Thies Foundation, the Messerli Foundation in Switzerland and WWF Germany, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions, NASA Ecological Forecasting Program, the Ecotone Telemetry company, the French National Research Agency, LANDTHIRST, grant REPOS awarded by the i-Site MUSE thanks to the “Investissements d’avenir” program, the ANR Mov-It project, the USDA Hatch Act Formula Funding, the Fondation Segre and North American and European Zoos listed at http://www.giantanteater.org/, the Utah Division of Wildlife Resources, the Yellowstone Forever and the National Park Service, Missouri Department of Conservation, Federal Aid in Wildlife Restoration Grant, and State University of New York, various donors to the Botswana Predator Conservation Program, data from collared caribou in the Northwest Territories were made available through funds from the Department of Environment and Natural Resources, Government of the Northwest Territories. The European Research Council Horizon2020, the British Ecological Society, the Paul Jones Family Trust, and the Lord Kelvin Adam Smith fund, the Tanzania Wildlife Research Institute and Tanzania National Parks. The Eastern Shoshone and Northern Arapahoe Fish and Game Department and the Wyoming State Veterinary Laboratory, the Alaska Department of Fish and Game, Kodiak Brown Bear Trust, Rocky Mountain Elk Foundation, Koniag Native Corporation, Old Harbor Native Corporation, Afognak Native Corporation, Ouzinkie Native Corporation, Natives of Kodiak Native Corporation and the State University of New York, College of Environmental Science and Forestry, and the Slovenia Hunters Association and Slovenia Forest Service. F.C. was partly supported by the Resident Visiting Researcher Fellowship, IMéRA/Aix-Marseille Université, Marseille. This work was partially funded by the Center of Advanced Systems Understanding (CASUS), which is financed by Germany’s Federal Ministry of Education and Research (BMBF) and by the Saxon Ministry for Science, Culture and Tourism (SMWK) with tax funds on the basis of the budget approved by the Saxon State Parliament. This article is a contribution of the COVID-19 Bio-Logging Initiative, which is funded in part by the Gordon and Betty Moore Foundation (GBMF9881) and the National Geographic Society.https://www.science.org/journal/sciencehj2023Mammal Research InstituteZoology and Entomolog

CMB-S4

We describe the stage 4 cosmic microwave background ground-based experiment CMB-S4

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