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Background: The aim of this study was to characterize the epidemiology of human seasonal coronaviruses (HCoVs) in southern Malawi., Methods: We tested for HCoVs 229E, OC43, NL63, and HKU1 using real-time polymerase chain reaction (PCR) on upper respiratory specimens from asymptomatic controls and individuals of all ages recruited through severe acute respiratory illness (SARI) surveillance at Queen Elizabeth Central Hospital, Blantyre, and a prospective influenza-like illness (ILI) observational study between 2011 and 2017. We modeled the probability of having a positive PCR for each HCoV using negative binomial models, and calculated pathogen-attributable fractions (PAFs)., Results: Overall, 8.8% (539/6107) of specimens were positive for ≥1 HCoV. OC43 was the most frequently detected HCoV (3.1% [191/6107]). NL63 was more frequently detected in ILI patients (adjusted incidence rate ratio [aIRR], 9.60 [95% confidence interval {CI}, 3.25-28.30]), while 229E (aIRR, 8.99 [95% CI, 1.81-44.70]) was more frequent in SARI patients than asymptomatic controls. In adults, 229E and OC43 were associated with SARI (PAF, 86.5% and 89.4%, respectively), while NL63 was associated with ILI (PAF, 85.1%). The prevalence of HCoVs was similar between children with SARI and controls. All HCoVs had bimodal peaks but distinct seasonality., Conclusions: OC43 was the most prevalent HCoV in acute respiratory illness of all ages. Individual HCoVs had distinct seasonality that differed from temperate settings., Competing Interests: Potential conflicts of interest. J. M. R. has received funding from UK Research and Innovation (UKRI) (MR/V038613/1). A. H. was supported by a Wellcome Trust Clinical PhD Fellowship (097464) and receives funding from UKRI, the Medical Research Council, British Society for Antimicrobial Chemotherapy, Wellcome Trust, and the Medical Research Foundation, unrelated to this work. S. A. was supported by a Wellcome Trust Clinical PhD Fellowship (099962). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Non-ventilator-associated hospital-acquired pneumonia (nv-HAP) is the most common healthcare-associated infection (HCAI), is associated with high mortality and morbidity and places a major burden on healthcare systems. Diagnosis currently relies on chest x-rays to confirm pneumonia and sputum cultures to determine the microbiological cause. This approach leads to over-diagnosis of pneumonia, rarely identifies a causative pathogen and perpetuates unnecessary and imprecise antibiotic use. The HAP-FAST study aims to evaluate the feasibility of a randomised trial to evaluate the clinical impact of low-dose, non-contrast-enhanced thoracic CT scans and rapid molecular sputum analysis using the BIOFIRE® FILMARRAY® pneumonia plus panel (FAPP) for patients suspected with nv-HAP., Methods and Analysis: The HAP-FAST feasibility study consists of a pilot randomised trial, a qualitative study, a costing analysis and exploratory analyses of clinical samples to investigate the immune-pathophysiology of HAP. Participants are identified and recruited from four acute hospitals in the Northwest of the UK. Using a Research Without Prior Consent model, the pilot trial will recruit 220 adult participants, with or without mental capacity, and with suspected HAP. HAP-FAST is a non-blinded, sequential, multiple assignment, randomised trial with two possible stages of randomisation: first, chest x-ray (CXR) or CT; second, if treated as nv-HAP, FAPP or standard microbiological processing alone (no FAPP). Pathogen-specific antibiotic guidance will be provided for FAPP results. Randomisation uses a web-based platform and followed up for 90 days. The feasibility of a future trial will be determined by assessing trial processes, outcome measures and patient and staff experiences., Ethics and Dissemination: This study has undergone combined review by the UK NHS Research Ethics Committee and Health Research Authority. Results will be disseminated via peer-reviewed journals, via the funders' website and through a range of media to engage the public., Trial Registration Number: NCT05483309., Competing Interests: Competing interests: The BIOFIRE® machines for each study site were loaned, free of charge by bioMérieux. FAPP test kits for running on those machines were also provided by bioMérieux. bioMérieux had no role in the content of the funding application, protocol, ethics application for this work nor will they have a role in handling or interpretation of the data or its dissemination. LT has received consulting fees from MHRA and from AstraZeneca and Synairgen, paid to the University of Liverpool; speakers’ fees from Eisai Ltd, and support for conference attendance from AstraZeneca. AH has received personal consulting fees from Pfizer and funding from Pfizer paid to the University of Liverpool for a public/practitioner engagement project., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Maize demand in Sub-Saharan Africa is expected to increase 2.3 times during the next 30 years driven by demographic and dietary changes. Over the past two decades, the area cropped with maize has expanded by 17 million hectares in the region, with limited yield increase. Following this trend could potentially result in further maize cropland expansion and the need for imports to satisfy domestic demand. Here, we use data collected from 14,773 smallholder fields in the region to identify agronomic practices that can improve farm yield gains. We find that agronomic practices related to cultivar selection, and nutrient, pest, and crop management can double on-farm yields and provide an additional 82 million tons of maize within current cropped area. Research and development investments should be oriented towards agricultural practices with proven capacity to raise maize yields in the region., (© 2024. The Author(s).)

Context: Agronomic data such as applied inputs, management practices, and crop yields are needed for assessing productivity, nutrient balances, resource use efficiency, as well as other aspects of environmental and economic performance of cropping systems. In many instances, however, these data are only available at a coarse level of aggregation or simply do not exist., Objectives: Here we developed an approach that identifies sites for agronomic data collection for a given crop and country, seeking a balance between minimizing data collection efforts and proper representation of the main crop producing areas., Methods: The developed approach followed a stratified sampling method based on a spatial framework that delineates major climate zones and crop area distribution maps, which guides selection of sampling areas (SA) until half of the national harvested area is covered. We provided proof of concept about the robustness of the approach using three rich databases including data on fertilizer application rates for maize, wheat, and soybean in Argentina, soybean in the USA, and maize in Kenya, which were collected via local experts (Argentina) and field surveys (USA and Kenya). For validation purposes, fertilizer rates per crop and nutrient derived at (sub-) national level following our approach were compared against those derived using all data collected from the whole country., Results: Application of the approach in Argentina, USA, and Kenya resulted in selection of 12, 28, and 10 SAs, respectively. For each SA, three experts or 20 fields were sufficient to give a robust estimate of average fertilizer rates applied by farmers. Average rates at national level derived from our approach compared well with those derived using the whole database ( ± 10 kg N, ± 2 kg P, ± 1 kg S, and ± 5 kg K per ha) requiring less than one third of the observations., Conclusions: The developed minimum crop data collection approach can fill the agronomic data gaps in a cost-effective way for major crop systems both in large- and small-scale systems., Significance: The proposed approach is generic enough to be applied to any crop-country combination to guide collection of key agricultural data at national and subnational levels with modest investment especially for countries that do not currently collect data., Competing Interests: The paper content has not been previously published nor is under consideration for publication elsewhere. All co-authors have contributed to the paper and have agreed to be listed as coauthors., (© 2024 The Authors.)

Health-care systems, food supply chains, and society in general are threatened by the inexorable rise of antimicrobial resistance. This threat is driven by many factors, one of which is inappropriate antimicrobial treatment. The ability of policy makers and leaders in health care, public health, regulatory agencies, and research and development to deliver frameworks for appropriate, sustainable antimicrobial treatment is hampered by a scarcity of tangible outcome-based measures of the damage it causes. In this Personal View, a mathematically grounded, outcome-based measure of antimicrobial treatment appropriateness, called imprecision, is proposed. We outline a framework for policy makers and health-care leaders to use this metric to deliver more effective antimicrobial stewardship interventions to future patient pathways. This will be achieved using learning antimicrobial systems built on public and practitioner engagement; solid implementation science; advances in artificial intelligence; and changes to regulation, research, and development. The outcomes of this framework would be more ecologically and organisationally sustainable patterns of antimicrobial development, regulation, and prescribing. We discuss practical, ethical, and regulatory considerations involved in the delivery of novel antimicrobial drug development, and policy and patient pathways built on artificial intelligence-augmented measures of antimicrobial treatment imprecision., Competing Interests: Declaration of interests AH declares consulting work for Pfizer outside of the submitted work. BW sits on the board of the York Health Economics Consortium. IB holds a senior investigator award with the National Institute for Health and Care Research and fees via University of Liverpool Consult service as Chief Data Scientist Advisor for AstraZeneca, outside of the submitted work. WH holds or has held research grants with United Kingdom Research and Innovation, EU, F2G, Spero Therapeutics, Antabio, Pfizer, Bugworks, Phico Therapeutics, BioVersys, Global Antibiotic Research & Development Partnership (GARDP), and NAEJA-RGM. WH is or has been a consultant for Appili Therapeutics, F2G, Spero Therapeutics, NAEJA-RGM, Centauri, Pfizer, Phico Therapeutics, Pulmocide, Amplyx, Mundipharma Research, and VenatoRx. WH is a member of the Specialist Advisory Committee for GARDP and the Specialty National co-lead for Infectious Diseases for the National Institute of Health Research. A-GM holds a ZonMW Rubicon Postdoctoral Fellowship Dutch Research Council. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The proliferation of various forms of artificial intelligence (AI) brings many opportunities to improve health care. AI models can harness complex evolving data, inform and augment human actions, and learn from health outcomes such as morbidity and mortality. The global public health challenge of antimicrobial resistance (AMR) needs large-scale optimisation of antimicrobial use and wider infection care, which could be enabled by carefully constructed AI models. As AI models become increasingly useful and robust, health-care systems remain challenging places for their deployment. An implementation gap exists between the promise of AI models and their use in patient and population care. Here, we outline an adaptive implementation and maintenance framework for AI models to improve antimicrobial use and infection care as a learning system. The roles of AMR problem identification, law and regulation, organisational support, data processing, and AI development, assessment, maintenance, and scalability in the implementation of AMR-targeted AI models are considered., Competing Interests: Declaration of interests AH declares consulting work for Pfizer outside the submitted work. HM received support for research not related to the current manuscript from UK Research and Innovation (UKRI), the Bill and Melinda Gates Foundation, and National Institutes of Health; is on the data safety monitoring board for the IMPROVE trial; is an interview panel member for the Wellcome career development award; and is a council member of the International Society for Infectious Diseases. IB holds a senior investigator award with the National Institute for Health and Care Research, and received personal fees and other fees from AstraZeneca outside the submitted work. WH holds or has held research grants with UKRI, EU, F2G, Spero Therapeutics, Antabio, Pfizer, Bugworks, Phico Therapeutics, BioVersys, Global Antibiotic Research & Development Partnership (GARDP), and NAEJA-RGM; is or has been a consultant for Appili Therapeutics, F2G, Spero Therapeutics, NAEJA-RGM, Centauri, Pfizer, Phico Therapeutics, Pulmocide, Amplyx, Mundipharma Research, and VenatoRx; is a member of the Specialist Advisory Committee for GARDP; and is the Specialty National Co-lead for Infectious Diseases for the National Institute of Health Research. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Higher-valency pneumococcal vaccines are anticipated. We aimed to describe serotype distribution and risk factors for vaccine-serotype community-acquired pneumonia (CAP) in the two years pre-SARS-CoV-2 pandemic., Methods: We conducted a prospective cohort study of adults hospitalised with CAP at three UK sites between 2018 and 2020. Pneumococcal serotypes were identified using a 24-valent urinary-antigen assay and blood cultures. Risk factors associated with vaccine-type pneumonia caused by serotypes in the 13-, 15- and 20-valent pneumococcal conjugate vaccines (PCV13, PCV15, PCV20) and 23-valent pneumococcal polysaccharide vaccine (PPV23) were determined from multivariable analysis., Findings: Of 1921 adults hospitalised with CAP, 781 (40.7%, 95% confidence intervals (CI) 38.5-42.9%) had pneumococcal pneumonia. A single PCV13-serotype was detected in 242 (31.0%, 95% CI 27.8-34.3%) pneumococcal CAP patients, mostly serotype 3 (171/242, 70.7%, 95% CI 64.5-76.0%). The additional two PCV15-serotypes were detected in 31 patients (4%, 95% CI 2.8-5.6%), and PCV20-non13-serotypes in 192 (24.6%), with serotype 8 most prevalent (123/192, 64.1%, 95% CI 57.1-70.5%). Compared to PCV13-serotype CAP, people with PCV20-non13 CAP were younger (median age 62 versus 72 years, p < 0.001) and less likely to be male (44% versus 61%, p = 0.01). PPV23-non13-serotypes were found in 252 (32.3%, 95% CI 29.1-35.6%) pneumococcal CAP patients., Interpretation: Despite mature infant pneumococcal programmes, the burden of PCV13-serotype pneumonia remains high in older adults, mainly due to serotype 3. PCV20-non13-serotype pneumonia is more likely in younger people with fewer pneumococcal risk factors., Funding: Unrestricted investigator-initiated research grant from Pfizer, United Kingdom; support from National Institute for Health Research (NIHR) Biomedical Research Centre, Nottingham., Competing Interests: WSL reports unrestricted investigator-initiated research funding from Pfizer to WSL's institution. WSL is Chair of COVID-19 Immunisation, Joint Committee of Vaccination and Immunisation (JCVI) (unpaid), is an unpaid expert panel member for NICE COVID-19 Guidelines, and is an unpaid member of the NHSE Specialist Commissioning Group for Covid-19 therapeutics. University of Nottingham paid costs to Liverpool University Foundation Hospital Trust for the completion of the field work; NF is an honorary member of LUHFT and of the department that received this funding. NF is PI on grants from Wellcome, MRC, EDTCP and Gates Foundation and is a co-investigator on awards from Seqirus CSl and from GSK for studies unrelated to this work, participates on 3 Data Safety Monitoring Boards for NIHR and MRC funded research trials in relation to pneumococcal challenge models outside the submitted work, and serves on the pneumococcal subcommittee of the JCVI UK. CT participated in a CMV vaccine advisory board meeting in May 2022, unrelated to the topic of this paper. SE declares participation in a Virtual Advisory Board for a pneumococcal project organised by Sanofi Pasteur SA unrelated to the submitted work. The UK Health Security Agency (UKHSA) received monies from the University of Nottingham from an unrestricted grant from Pfizer for this work. The Vaccine Preventable Bacteria Section of UKHSA has received grants from Pfizer for investigator led research unrelated to the current project. The UKHSA provides vaccine manufacturers (GlaxoSmithKline (GSK), MSD, Pfizer) with post marketing surveillance reports on vaccine-preventable disease, including pneumococcal infections for which a cost recovery charge is made and which is unrelated to the submitted work. No other authors declare competing interests., (© 2023 The Authors.)

Efficient decision-making requires accounting for sources of uncertainty (noise, or variability). Many studies have shown how the nervous system is able to account for perceptual uncertainty (noise, variability) that arises from limitations in its own abilities to encode perceptual stimuli. However, many other sources of uncertainty exist, reflecting for example variability in the behaviour of other agents or physical processes. Here we review previous studies on decision making under uncertainty as a function of the different types of uncertainty that the nervous system encounters, showing that noise that is intrinsic to the perceptual system can often be accounted for near-optimally (i.e. not statistically different from optimally), whereas accounting for other types of uncertainty can be much more challenging. As an example, we present a study in which participants made decisions about multisensory stimuli with both intrinsic (perceptual) and extrinsic (environmental) uncertainty and show that the nervous system accounts for these differently when making decisions: they account for internal uncertainty but under-account for external. Human perceptual systems may be well equipped to account for intrinsic (perceptual) uncertainty because, in principle, they have access to this. Accounting for external uncertainty is more challenging because this uncertainty must be learned. This article is part of the theme issue 'Decision and control processes in multisensory perception'.

Background: Despite children and young people (CYP) having a low risk for severe coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated., Methods: A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31 October 2021 (to exclude vaccinated populations) was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalization and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity., Findings: The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP ( n = 793) and CYP in general population ( n = 102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%), and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared with CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies., Interpretation: This is the only up-to-date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalized cohorts alone and included 35% studies from low- and middle-income countries. Future research is required to characterize individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes., Systematic Review Registration: PROSPERO identifier, CRD42021278598., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Greenan-Barrett, Aston, Deakin and Ciurtin.)

Purpose of the Review: To describe important recent developments in the treatment of multidrug resistant tuberculosis (MDR-TB)., Recent Findings: In the last decade, novel and repurposed antituberculosis drugs have transformed MDR-TB treatment with improved rates of treatment success, better tolerability and safety and reduced duration. As recently as 2016, standard care relied on up to seven drugs for 24 months with treatment success no better than 70%. Seven drug shorter so-called "Bangladesh" style regimens subsequently achieved similar or better results at a duration of 9-12 months but concerns about first-line resistance additional to rifampicin hampered global uptake. After conditional approval in 2012, the novel agent bedaquiline was demonstrated to improve outcomes and reduce mortality when used in longer and shorter regimens, resulting in the replacement of injectable agents. In the last 2 years, clinical trials of all-oral 6-month three or four drug regimens containing bedaquiline, pretomanid and linezolid have shown superior efficacy against both longer and shorter traditional regimens, resulting in major changes in WHO guidance., Summary: Although some concerns around safety and emergent bedaquiline resistance remain to be fully addressed, 6-month all oral regimens promise to transform the treatment of people with MDR-TB worldwide., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

When the illumination falling on a surface change, so does the reflected light. Despite this, adult observers are good at perceiving surfaces as relatively unchanging-an ability termed colour constancy. Very few studies have investigated colour constancy in infants, and even fewer in children. Here we asked whether there is a difference in colour constancy between children and adults; what the developmental trajectory is between six and 11 years; and whether the pattern of constancy across illuminations and reflectances differs between adults and children. To this end, we developed a novel, child-friendly computer-based object selection task. In this, observers saw a dragon's favourite sweet under a neutral illumination and picked the matching sweet from an array of eight seen under a different illumination (blue, yellow, red, or green). This set contained a reflectance match (colour constant; perfect performance) and a tristimulus match (colour inconstant). We ran two experiments, with two-dimensional scenes in one and three-dimensional renderings in the other. Twenty-six adults and 33 children took part in the first experiment; 26 adults and 40 children took part in the second. Children performed better than adults on this task, and their performance decreased with age in both experiments. We found differences across illuminations and sweets, but a similar pattern across both age groups. This unexpected finding might reflect a real decrease in colour constancy from childhood to adulthood, explained by developmental changes in the perceptual and cognitive mechanisms underpinning colour constancy, or differences in task strategies between children and adults. HIGHLIGHTS: Six- to 11-year-old children demonstrated better performance than adults on a colour constancy object selection task. Performance decreased with age over childhood. These findings may indicate development of cognitive strategies used to overcome automatic colour constancy mechanisms., (© 2022 The Authors. Developmental Science published by John Wiley & Sons Ltd.)

Color constancy is the perceptual stability of surface colors under temporal changes in the illumination spectrum. The illumination discrimination task (IDT) reveals worse discrimination for "bluer" illumination changes in normal-trichromatic observers (changes towards cooler color temperatures on the daylight chromaticity locus), indicating greater stability of scene colors or better color constancy, compared with illumination changes in other chromatic directions. Here, we compare the performance of individuals with X-linked color-vision deficiencies (CVDs) to normal trichromats on the IDT performed in an immersive setting with a real scene illuminated by spectrally tunable LED lamps. We determine discrimination thresholds for illumination changes relative to a reference illumination (D65) in four chromatic directions, roughly parallel and orthogonal to the daylight locus. We find, using both a standard CIELUV metric and a cone-contrast metric tailored to distinct CVD types, that discrimination thresholds for daylight changes do not differ between normal trichromats and CVD types, including dichromats and anomalous trichromats, but thresholds for atypical illuminations do differ. This result extends a previous report of illumination discrimination ability in dichromats for simulated daylight changes in images. In addition, using the cone-contrast metric to compare thresholds for bluer and yellower daylight changes with those for unnatural redder and greener changes, we suggest that reduced sensitivity to daylight changes is weakly preserved in X-linked CVDs.

Background: Immunocompromised patients may be at higher risk of mortality if hospitalised with Coronavirus Disease 2019 (COVID-19) compared with immunocompetent patients. However, previous studies have been contradictory. We aimed to determine whether immunocompromised patients were at greater risk of in-hospital death and how this risk changed over the pandemic., Methods and Findings: We included patients > = 19 years with symptomatic community-acquired COVID-19 recruited to the ISARIC WHO Clinical Characterisation Protocol UK prospective cohort study. We defined immunocompromise as immunosuppressant medication preadmission, cancer treatment, organ transplant, HIV, or congenital immunodeficiency. We used logistic regression to compare the risk of death in both groups, adjusting for age, sex, deprivation, ethnicity, vaccination, and comorbidities. We used Bayesian logistic regression to explore mortality over time. Between 17 January 2020 and 28 February 2022, we recruited 156,552 eligible patients, of whom 21,954 (14%) were immunocompromised. In total, 29% (n = 6,499) of immunocompromised and 21% (n = 28,608) of immunocompetent patients died in hospital. The odds of in-hospital mortality were elevated for immunocompromised patients (adjusted OR 1.44, 95% CI [1.39, 1.50], p < 0.001). Not all immunocompromising conditions had the same risk, for example, patients on active cancer treatment were less likely to have their care escalated to intensive care (adjusted OR 0.77, 95% CI [0.7, 0.85], p < 0.001) or ventilation (adjusted OR 0.65, 95% CI [0.56, 0.76], p < 0.001). However, cancer patients were more likely to die (adjusted OR 2.0, 95% CI [1.87, 2.15], p < 0.001). Analyses were adjusted for age, sex, socioeconomic deprivation, comorbidities, and vaccination status. As the pandemic progressed, in-hospital mortality reduced more slowly for immunocompromised patients than for immunocompetent patients. This was particularly evident with increasing age: the probability of the reduction in hospital mortality being less for immunocompromised patients aged 50 to 69 years was 88% for men and 83% for women, and for those >80 years was 99% for men and 98% for women. The study is limited by a lack of detailed drug data prior to admission, including steroid doses, meaning that we may have incorrectly categorised some immunocompromised patients as immunocompetent., Conclusions: Immunocompromised patients remain at elevated risk of death from COVID-19. Targeted measures such as additional vaccine doses, monoclonal antibodies, and nonpharmaceutical preventive interventions should be continually encouraged for this patient group., Trial Registration: ISRCTN 66726260., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: LT declares a lecture fee paid to his institution from Eisai ltd. CP reports research grants from Pfizer, Daiichi Sankyo and Seagen, consulting fees from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, SeaGen and Eli Lilly, and payment for lectures from Pfizer, Novartis and Eisai ltd. PO declares fees from Affnivax, Oxford Immunotech, Nestle, Pfizer and Janessen for consulting or chairing a symposium, paid to Imperial College. MGS is chair of the infectious disease advisory board for Integrum Scientific, director of MedEx solutions ltd, participated in the DSMB for Pfizer COVID-19 vaccine trials, and was donated an investigational medicinal product by Chiesi Farmaceutici S.p.A. MGS and PJMO sat on HMG UK New Emerging Respiratory Virus Threats Advisory Group (NERVTAG). MGS sat on HMG UK Scientific Advisory Group for Emergencies (SAGE), COVID-19 Response from March 2020 to March 2022., (Copyright: © 2023 Turtle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Advanced Laser Interferometer Gravitational-wave Observatory (LIGO A+) is a major upgrade to LIGO-the Laser Interferometer Gravitational-wave Observatory. For the A+ project, we have developed, produced, and characterized sensors and electronics to interrogate new optical suspensions designed to isolate optics from vibrations. The central element is a displacement sensor with an integrated electromagnetic actuator known as a BOSEM (Birmingham Optical Sensor and ElectroMagnetic actuator) and its readout and drive electronics required to integrate them into LIGO's control and data system. In this paper, we report on the improvements to the sensors and the testing procedures undertaken to meet the enhanced performance requirements set out by the A+ upgrade to the detectors. The best devices reach a noise level of 4.5 ×10 -11 m/Hz at a measurement frequency of 1 Hz, an improvement of 6.7 times over standard devices.

Reliability-weighted averaging of multiple perceptual estimates (or cues) can improve precision. Research suggests that newly learned statistical associations can be rapidly integrated in this way for efficient decision-making. Yet, it remains unclear if the integration of newly learned statistics into decision-making can directly influence perception, rather than taking place only at the decision stage. In two experiments, we implicitly taught observers novel associations between shape and color. Observers made color matches by adjusting the color of an oval to match a simultaneously presented reference. As the color of the oval changed across trials, so did its shape according to a novel mapping of axis ratio to color. Observers showed signatures of reliability-weighted averaging-a precision improvement in both experiments and reweighting of the newly learned shape cue with changes in uncertainty in Experiment 2. To ask whether this was accompanied by perceptual effects, Experiment 1 tested for forced fusion by measuring color discrimination thresholds with and without incongruent novel cues. Experiment 2 tested for a memory color effect, observers adjusting the color of ovals with different axis ratios until they appeared gray. There was no evidence for forced fusion and the opposite of a memory color effect. Overall, our results suggest that the ability to quickly learn novel cues and integrate them with familiar cues is not immediately (within the short duration of our experiments and in the domain of color and shape) accompanied by common perceptual effects.

People bereaved by suicide are affected psychologically and physically and may be at greater risk of taking their own lives. Whilst researchers have explored the impact of suicide on family members and friends, the area of colleague suicide has been neglected and postvention guidance for supporting surviving colleagues is often poorly developed. This critical integrative review explored the impact of colleague suicide on surviving co-workers and reviewed postvention guidance for workplaces. Systematic searches found 17 articles that met the inclusion criteria. Articles were appraised for quality and extracted data were analysed using a thematic network method. Article quality was moderate. Two global themes were developed: impact of a colleague suicide comprised themes of 'suicide loss in the workplace'; 'professional identities and workplace roles'; 'perceptions of professional uniqueness'; and 'professional abandonment and silencing'. Postvention following a colleague suicide comprised 'individualised responses'; 'the dual function of stigma'; and 'complex pressure on managers'. A unifying global network 'after a colleague suicide' describes the relationships between all themes. A series of disconnects between existing postvention guidance and the needs of impacted workers are discussed. This review demonstrates the need for robust, systemic postvention for colleagues impacted by the complex issue of colleague suicide.

We investigated the claims of EnChroma that their notch filters aid chromatic discrimination in color-vision deficiencies (CVD). Few research studies have addressed these claims and reports are still inconclusive, mainly due to small sample sizes. We here add to previous research finding little evidence to support the benefits of EnChroma lenses. Comparing the performance of 86 well-categorized CVD observers and 24 controls on two clinical tests we report no overall improvement when EnChroma lenses were worn. In line with previous studies, our results imply an improvement in discrimination for some colors while worsening discrimination for others. A model was constructed computing discrimination changes for different groups of ideal observers corroborating our behavioral outcomes. Taken together, our results do not support the use of EnChroma notch filters for the improvement of color discrimination in CVD.

Introduction: Sepsis is a common, potentially life-threatening complication of infection. The optimal treatment for sepsis includes prompt antibiotics and intravenous fluids, facilitated by its early and accurate recognition. Currently, clinicians identify and assess severity of suspected sepsis using validated clinical scoring systems. In England, the National Early Warning Score 2 (NEWS2) has been mandated across all National Health Service (NHS) trusts and ambulance organisations. Like many clinical scoring systems, NEWS2 should not be used without clinical judgement to determine either the level of acuity or a diagnosis. Despite this, there is a tendency to overemphasise the score in isolation in patients with suspected infection, leading to the overprescription of antibiotics and potentially treatment-related complications and rising antimicrobial resistance. The biomarker procalcitonin (PCT) has been shown to be useful in specific circumstances to support appropriate antibiotics prescribing by identifying bacterial infection. PCT is not routinely used in the care of undifferentiated patients presenting to emergency departments (EDs), and the evidence base of its optimal usage is poor. The PROcalcitonin and NEWS2 evaluation for Timely identification of sepsis and Optimal (PRONTO) study is a randomised controlled trial (RCT) in adults with suspected sepsis presenting to the ED to compare standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment with standard clinical management based on NEWS2 scoring alone and compare if this approach reduces prescriptions of antibiotics without increasing mortality., Methods and Analysis: PRONTO is a parallel two-arm open-label individually RCT set in up to 20 NHS EDs in the UK with a target sample size of 7676 participants. Participants will be randomised in a ratio of 1:1 to standard clinical management based on NEWS2 scoring or standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment. We will compare whether the addition of PCT measurement to NEWS2 scoring can lead to a reduction in intravenous antibiotic initiation in ED patients managed as suspected sepsis, with at least no increase in 28-day mortality compared with NEWS2 scoring alone (in conjunction with local standard care pathways). PRONTO has two coprimary endpoints: initiation of intravenous antibiotics at 3 hours (superiority comparison) and 28-day mortality (non-inferiority comparison). The study has an internal pilot phase and group-sequential stopping rules for effectiveness and futility/safety, as well as a qualitative substudy and a health economic evaluation., Ethics and Dissemination: The trial protocol was approved by the Health Research Authority (HRA) and NHS Research Ethics Committee (Wales REC 2, reference 20/WA/0058). In England and Wales, the law allows the use of deferred consent in approved research situations (including ED studies) where the time dependent nature of intervention would not allow true informed consent to be obtained. PRONTO has approval for a deferred consent process to be used. Findings will be disseminated through peer-reviewed journals and presented at scientific conferences., Trial Registration Number: ISRCTN54006056., Competing Interests: Competing interests: EC is co-CI for the BATCH Trial (HTA 15/188/42) and the PEACH study (HTA Project: NIHR132254) on PCT use, and member of NICE Diagnostic advisory committee (2014–2020), and NICE Sepsis guideline development committee (2014-6). All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mature perceptual systems can learn new arbitrary sensory signals (novel cues) to properties of the environment, but little is known about the extent to which novel cues are integrated into normal perception. In normal perception, multiple uncertain familiar cues are combined, often near-optimally (reliability-weighted averaging), to increase perceptual precision. We trained observers to use abstract novel cues to estimate horizontal locations of hidden objects on a monitor. In experiment 1, 4 groups of observers each learned to use a different novel cue. All groups benefited from a suboptimal but significant gain in precision using novel and familiar cues together after short-term training (3 ∼1.5 hr sessions), extending previous reports of novel-familiar cue combination. In experiment 2, we tested whether 2 novel cues may also be combined with each other. One pair of novel cues could be combined to improve precision but the other could not, at least not after 3 sessions of repeated training. Overall, our results provide extensive evidence that novel cues can be learned and combined with familiar cues to enhance perception, but mixed evidence for whether perceptual and decision-making systems can extend this ability to the combination of multiple novel cues with only short-term training. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Observers in perceptual tasks are often reported to combine multiple sensory cues in a weighted average that improves precision-in some studies, approaching statistically optimal (Bayesian) weighting, but in others departing from optimality, or not benefitting from combined cues at all. To correctly conclude which combination rules observers use, it is crucial to have accurate measures of their sensory precision and cue weighting. Here, we present a new approach for accurately recovering these parameters in perceptual tasks with continuous responses. Continuous responses have many advantages, but are susceptible to a central tendency bias, where responses are biased towards the central stimulus value. We show that such biases lead to inaccuracies in estimating both precision gains and cue weightings, two key measures used to assess sensory cue combination. We introduce a method that estimates sensory precision by regressing continuous responses on targets and dividing the variance of the residuals by the squared slope of the regression line, "correcting-out" the error introduced by the central bias and increasing statistical power. We also suggest a complementary analysis that recovers the sensory cue weights. Using both simulations and empirical data, we show that the proposed methods can accurately estimate sensory precision and cue weightings in the presence of central tendency biases. We conclude that central tendency biases should be (and can easily be) accounted for to consistently capture Bayesian cue combination in continuous response data., (© 2021. The Author(s).)

Background: NHS England recommends non-invasive continuous positive airway pressure (CPAP) as a possible treatment for type 1 respiratory failure associated with COVID-19 pneumonitis, either to avoid intubation or as a ceiling of care. However, data assessing this strategy are sparse, especially for the use of CPAP as a ceiling of care, and particularly when delivered outside of a traditional critical care environment. We describe a cohort of patients from Liverpool, UK, who received CPAP on a dedicated respiratory surge unit at the start of the second wave of the COVID-19 pandemic in UK., Methods: Retrospective cohort analysis of consecutive patients receiving CPAP for the treatment of respiratory failure secondary to COVID-19 on the respiratory surge unit at the Royal Liverpool Hospital, Liverpool, UK from 21 September until 30 November 2020., Results: 88 patients were included in the analysis. 56/88 (64%) were deemed suitable for escalation to invasive mechanical ventilation (IMV) and received CPAP as a trial; 32/88 (36%) received CPAP as a ceiling of care. Median age was 63 years (IQR: 56-74) and 58/88 (66%) were men. Median SpO 2 /FiO 2 immediately prior to CPAP initiation was 95 (92-152). Among patients for escalation to IMV, the median time on CPAP was 6 days (IQR 4-7) and survival at day 30 was 84% (47/56) with 14/56 (25%) escalated to IMV. Of those patients for whom CPAP was ceiling of care, the median duration of CPAP was 9 days (IQR 7-11) and 18/32 (56%) survived to day 30. Pulmonary barotrauma occurred in 9% of the cohort. There were no associations found on multivariant analysis that were associated with all-cause 30-day mortality., Conclusions: With adequate planning and resource redistribution, CPAP may be delivered effectively outside of a traditional critical care setting for the treatment of respiratory failure due to COVID-19. Clinicians delivering CPAP to patients with COVID-19 pneumonitis should be alert to the dangers of pulmonary barotrauma. Among patients who are for escalation of care, the use of CPAP may avoid the need for IMV in some patients. Our data support the NHS England recommendation to consider CPAP as a ceiling of care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The emergence and rapid spread of COVID-19 have caused widespread and catastrophic public health and economic impact, requiring governments to restrict societal activity to reduce the spread of the disease. The role of household transmission in the population spread of SARS-CoV-2, and of host immunity in limiting transmission, is poorly understood. This paper describes a protocol for a prospective observational study of a cohort of households in Liverpool City Region, UK, which addresses the transmission of SARS-CoV-2 between household members and how immunological response to the infection changes over time., Methods and Analysis: Households in the Liverpool City Region, in which members have not previously tested positive for SARS-CoV-2 with a nucleic acid amplification test, are followed up for an initial period of 12 weeks. Participants are asked to provide weekly self-throat and nasal swabs and record their activity and presence of symptoms. Incidence of infection and household secondary attack rates of COVID-19 are measured. Transmission of SARS-CoV-2 will be investigated against a range of demographic and behavioural variables. Blood and faecal samples are collected at several time points to evaluate immune responses to SARS-CoV-2 infection and prevalence and risk factors for faecal shedding of SARS-CoV-2, respectively., Ethics and Dissemination: The study has received approval from the National Health Service Research Ethics Committee; REC Reference: 20/HRA/2297, IRAS Number: 283 464. Results will be disseminated through scientific conferences and peer-reviewed open access publications. A report of the findings will also be shared with participants. The study will quantify the scale and determinants of household transmission of SARS-CoV-2. Additionally, immunological responses before and during the different stages of infection will be analysed, adding to the understanding of the range of immunological response by infection severity., Competing Interests: Competing interests: MW is funded under a grant from Astra Zeneca and University of Liverpool for an unrelated project., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The COVID-19 pandemic has led to a dramatic increase in patients presenting with type 1 respiratory failure. In order to protect our limited critical care capacity, we rapidly developed a new ward-based inpatient continuous positive airway pressure (CPAP) service with direct input from the respiratory, infectious diseases and critical care teams. Close collaboration between these specialties and new innovative solutions were required to facilitate this. CPAP equipment (normally reserved for domiciliary care) was adapted to reduce the pressure on our strained oxygen infrastructure. Side rooms on the infectious diseases ward were swiftly converted into new negative pressure areas using temporary installed ventilatory equipment, reducing the viral aerosol risk for staff. Novel patient monitoring solutions were used to protect staff while also ensuring patient safety. Staff training and specialist oversight was organised within days. The resulting service was successful, with over half (17/26 (65%)) of patients avoiding invasive ventilation., (© Royal College of Physicians 2021. All rights reserved.)

Previous studies suggest that to achieve color constancy, the human visual system makes use of multiple cues, including a priori assumptions about the illumination ("daylight priors"). Specular highlights have been proposed to aid constancy, but the evidence for their usefulness is mixed. Here, we used a novel cue-combination approach to test whether the presence of specular highlights or the validity of a daylight prior improves illumination chromaticity estimates, inferred from achromatic settings, to determine whether and under which conditions either cue contributes to color constancy. Observers made achromatic settings within three-dimensional rendered scenes containing matte or glossy shapes, illuminated by either daylight or nondaylight illuminations. We assessed both the variability of these settings and their accuracy, in terms of the standard color constancy index (CCI). When a spectrally uniform background was present, neither CCIs nor variability improved with specular highlights or daylight illuminants (Experiment 1). When a Mondrian background was introduced, CCIs decreased overall but were higher for scenes containing glossy, as opposed to matte, shapes (Experiments 2 and 3). There was no overall reduction in variability of settings and no benefit for scenes illuminated by daylights. Taken together, these results suggest that the human visual system indeed uses specular highlights to improve color constancy but only when other cues, such as from the local surround, are weakened.

The colors that people see depend not only on the surface properties of objects but also on how these properties interact with light as well as on how light reflected from objects interacts with an individual's visual system. Because individual visual systems vary, the same visual stimulus may elicit different perceptions from different individuals. #thedress phenomenon drove home this point: different individuals viewed the same image and reported it to be widely different colors: blue and black versus white and gold. This phenomenon inspired a collection of demonstrations presented at the Vision Sciences Society 2015 Meeting which showed how spatial and temporal manipulations of light spectra affect people's perceptions of material colors and illustrated the variability in individual color perception. The demonstrations also explored the effects of temporal alterations in metameric lights, including Maxwell's Spot, an entoptic phenomenon. Crucially, the demonstrations established that #thedress phenomenon occurs not only for images of the dress but also for the real dress under real light sources of different spectral composition and spatial configurations.

Nonexcisional facial skin tightening has long been an elusive goal in aesthetic surgery. The "treatment gap" includes cases who are not "severe" enough for excisions surgery but not "mild" enough for most traditional noninvasive aesthetic modalities. In this retrospective review, we present the largest evaluation to date of radiofrequency (RF) skin tightening technology combination including bipolar RF (FaceTite; InMode) and fractional bipolar RF (Fractora modified to Morpheus8; InMode)., Methods: A multicenter retrospective study was conducted between January 2013 and December 2018 using a combination of bipolar RF and fractional bipolar RF for the treatment of facial aging. Data collection included demographic information, Baker Face/Neck Classification, amount of energy used, adverse events, and patient satisfaction. Four cadaver dissections were also conducted to correlate the underlying neuromuscular anatomy with RF treatment of the lower face and neck., Results: Two hundred forty-seven patients (234 women and 13 men) were included in the study. Average age was 55.1 years (SD, ±8), body mass index was 24.3 (±2.4), and 9% (23/247) of patients were active smokers at the time of treatment. Patients had an average Baker Face/Neck Classification score of 3.1 (SD, ±1.4). The procedure was performed under local anesthesia in 240/247 cases (97.2%). Patients objectively improved their Baker Face/Neck Classification score by 1.4 points (SD, ±1.1). Ninety-three percent of patients indicated that they were pleased with their results and would undergo the procedure again. Complications recorded for our cohort included prolonged swelling >6 weeks (4.8%, 12/247), hardened area >12 weeks (3.2%, 8/247), and marginal mandibular neuropraxia (1.2%, 3/247), which all resolved without further intervention. When considering possible control variables, age seems to be a significant factor. That is, older patients were more likely to benefit from a larger magnitude of the treatment effect (as demonstrated by a decrease in the Baker rating from pre- to posttreatment) when compared with younger patients. However, both groups did demonstrate significant improvements across time., Conclusion: While this combination RF treatment (FaceTite bipolar RF and fractional bipolar RF) does not aim to replace a facelift/necklift in appropriate candidates, it does broaden the plastic surgeons' armamentarium to potentially fill a treatment gap., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19)., Purpose: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19., Data Sources: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020., Study Selection: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included., Data Extraction: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews)., Data Synthesis: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs., Limitation: Direct studies in COVID-19 are limited and poorly reported., Conclusion: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers., Primary Funding Source: World Health Organization. (PROSPERO: CRD42020178187).

The aim of this case series is to describe and evaluate our experience of continuous positive airway pressure (CPAP) to treat type 1 respiratory failure in patients with COVID-19. CPAP was delivered in negative pressure rooms in the newly repurposed infectious disease unit. We report a cohort of 24 patients with type 1 respiratory failure and COVID-19 admitted to the Royal Liverpool Hospital between 1 April and 30 April 2020. Overall, our results were positive; we were able to safely administer CPAP outside the walls of a critical care or high dependency unit environment and over half of patients (58%) avoided mechanical ventilation and a total of 19 out of 24 (79%) have survived and been discharged from our care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sepsis guidelines are widely used in high-income countries and intravenous fluids are an important supportive treatment modality. However, fluids have been harmful in intervention trials in low-income countries, most notably in sub-Saharan Africa. We assessed the relevance, quality and applicability of available guidelines for the fluid management of adult patients with sepsis in this region., Methods: We identified sepsis guidelines by systematic review with broad search terms, duplicate screening and data extraction. We included peer-reviewed publications with explicit relevance to sepsis and fluid therapy. We excluded those designed exclusively for specific aetiologies of sepsis, for limited geographic locations, or for non-adult populations. We used the AGREE II tool to assess the quality of guideline development, performed a narrative synthesis and used theoretical case scenarios to assess practical applicability to everyday clinical practice in resource-constrained settings., Results: Published sepsis guidelines are heterogeneous in sepsis definition and in quality: 8/10 guidelines had significant deficits in applicability, particularly with reference to resource considerations in low-income settings. Indications for intravenous fluid were hypotension (8/10), clinical markers of hypoperfusion (6/10) and lactataemia (3/10). Crystalloids were overwhelmingly recommended (9/10). Suggested volumes varied; 5/10 explicitly recommended "fluid challenges" with reassessment, totalling between 1 L and 4 L during initial resuscitation. Fluid balance, including later de-escalation of therapy, was not specifically described in any. Norepinephrine was the preferred initial vasopressor (5/10), specifically targeted to MAP > 65 mmHg (3/10), with higher values suggested in pre-existing hypertension (1/10). Recommendations for guidelines were almost universally derived from evidence in high-income countries. None of the guidelines suggested any refinement for patients with malnutrition., Conclusions: Widely used international guidelines contain disparate recommendations on intravenous fluid use, lack specificity and are largely unattainable in low-income countries given available resources. A relative lack of high-quality evidence from sub-Saharan Africa increases reliance on recommendations which may not be relevant or implementable.

Prior knowledge can help observers in various situations. Adults can simultaneously learn two location priors and integrate these with sensory information to locate hidden objects. Importantly, observers weight prior and sensory (likelihood) information differently depending on their respective reliabilities, in line with principles of Bayesian inference. Yet, there is limited evidence that observers actually perform Bayesian inference, rather than a heuristic, such as forming a look-up table. To distinguish these possibilities, we ask whether previously learned priors will be immediately integrated with a new, untrained likelihood. If observers use Bayesian principles, they should immediately put less weight on the new, less reliable, likelihood ("Bayesian transfer"). In an initial experiment, observers estimated the position of a hidden target, drawn from one of two distinct distributions, using sensory and prior information. The sensory cue consisted of dots drawn from a Gaussian distribution centered on the true location with either low, medium, or high variance; the latter introduced after block three of five to test for evidence of Bayesian transfer. Observers did not weight the cue (relative to the prior) significantly less in the high compared to medium variance condition, counter to Bayesian predictions. However, when explicitly informed of the different prior variabilities, observers placed less weight on the new high variance likelihood ("Bayesian transfer"), yet, substantially diverged from ideal. Much of this divergence can be captured by a model that weights sensory information, according only to internal noise in using the cue. These results emphasize the limits of Bayesian models in complex tasks.

Neisseria meningitidis is the causative agent of meningococcal meningitis and sepsis and remains a significant public health problem in many countries. Efforts to develop a comprehensive vaccine against serogroup B meningococci have focused on the use of surface-exposed outer membrane proteins. Here we report the use of virus-like particles derived from the core protein of Hepatitis B Virus, HBc, to incorporate antigen domains derived from Factor H binding protein (FHbp) and the adhesin NadA. The extracellular domain of NadA was inserted into the major immunodominant region of HBc, and the C-terminal domain of FHbp at the C-terminus (CFHbp), creating a single polypeptide chain 3.7-fold larger than native HBc. Remarkably, cryoelectron microscopy revealed that the construct formed assemblies that were able to incorporate both antigens with minimal structural changes to native HBc. Electron density was weak for NadA and absent for CFHbp, partly attributable to domain flexibility. Following immunization of mice, three HBc fusions (CFHbp or NadA alone, NadA + CFHbp) were able to induce production of IgG1, IgG2a and IgG2b antibodies reactive against their respective antigens at dilutions in excess of 1:18,000. However, only HBc fusions containing NadA elicited the production of antibodies with serum bactericidal activity. It is hypothesized that this improved immune response is attributable to the adoption of a more native-like folding of crucial conformational epitopes of NadA within the chimeric VLP. This work demonstrates that HBc can incorporate insertions of large antigen domains but that maintenance of their three-dimensional structure is likely to be critical in obtaining a protective response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We measured discrimination thresholds for illumination changes along different chromatic directions starting from chromatically biased reference illuminations. Participants viewed a Mondrian-papered scene illuminated by LED lamps. The scene was first illuminated by a reference illumination, followed by two comparisons. One comparison matched the reference (the target); the other (the test) varied from the reference, nominally either bluer, yellower, redder, or greener. The participant's task was to correctly select the target. A staircase procedure found thresholds for discrimination of an illumination change along each axis of chromatic change. Nine participants completed the task for five different reference illumination conditions (neutral, blue, yellow, red, and green). We find that relative discrimination thresholds for different chromatic directions of illumination change vary with the reference illumination. For the neutral reference, there is a trend for thresholds to be highest in the bluer illumination-change direction, replicating our previous reports of a "blue bias" for neutral reference illuminations. For the four chromatic references (blue, yellow, red, and green), the change in illumination toward the neutral reference is less well discriminated than changes in the other directions: a "neutral bias." The results have implications for color constancy: In considering the stability of surface appearance under changes in illumination, both the starting chromaticity of the illumination and direction of change must be considered, as well as the chromatic characteristics of the surface reflectance ensemble. They also suggest it will be worthwhile to explore whether and how the human visual system has internalized the statistics of natural illumination changes.

Previous studies have shown that humans can discriminate spectral changes in illumination and that this sensitivity depends both on the chromatic direction of the illumination change and on the ensemble of surfaces in the scene. These studies, however, always used stimulus scenes with a fixed surface-reflectance layout. Here we compared illumination discrimination for scenes in which the surface reflectance layout remains fixed (fixed-surfaces condition) to those in which surface reflectances were shuffled randomly across scenes, but with the mean scene reflectance held approximately constant (shuffled-surfaces condition). Illumination discrimination thresholds in the fixed-surfaces condition were commensurate with previous reports. Thresholds in the shuffled-surfaces condition, however, were considerably elevated. Nonetheless, performance in the shuffled-surfaces condition exceeded that attainable through random guessing. Analysis of eye fixations revealed that in the fixed-surfaces condition, low illumination discrimination thresholds (across observers) were predicted by low overall fixation spread and high consistency of fixation location and fixated surface reflectances across trial intervals. Performance in the shuffled-surfaces condition was not systematically related to any of the eye-fixation characteristics we examined for that condition, but was correlated with performance in the fixed-surfaces condition.

Background: Four million people die each year from diseases caused by exposure to household air pollution. There is an association between exposure to household air pollution and pneumonia in children (half a million attributable deaths a year); however, whether this is true in adults is unknown. We conducted a case-control study in urban Malawi to examine the association between exposure to household air pollution and pneumonia in adults. Methods: Hospitalized patients with radiologically confirmed pneumonia (cases) and healthy community controls underwent 48 hours of ambulatory and household particulate matter (µg/m 3 ) and carbon monoxide (ppm) exposure monitoring. Multivariate logistic regression, stratified by HIV status, explored associations between these and other potential risk factors with pneumonia. Results: 145 (117 HIV-positive; 28 HIV-negative) cases and 253 (169 HIV-positive; 84 HIV-negative) controls completed follow up. We found no evidence of association between household air pollution exposure and pneumonia in HIV-positive (e.g. ambulatory particulate matter adjusted odds ratio [aOR] 1.00 [95% CI 1.00-1.01, p=0.141]) or HIV-negative (e.g. ambulatory particulate matter aOR 1.00 [95% CI 0.99-1.01, p=0.872]) participants. Chronic respiratory disease was associated with pneumonia in both HIV-positive (aOR 28.07 [95% CI 9.29-84.83, p<0.001]) and HIV-negative (aOR 104.27 [95% CI 12.86-852.35, p<0.001]) participants. Conclusions: We found no evidence that exposure to household air pollution is associated with pneumonia in Malawian adults. In contrast, chronic respiratory disease was strongly associated with pneumonia., Competing Interests: Competing interests: No competing interests were disclosed.

The disagreement between people who named #theDress (the Internet phenomenon of 2015) "blue and black" versus "white and gold" is thought to be caused by individual differences in color constancy. It is hypothesized that observers infer different incident illuminations, relying on illumination "priors" to overcome the ambiguity of the image. Different experiences may drive the formation of different illumination priors, and these may be indicated by differences in chronotype. We assess this hypothesis, asking whether matches to perceived illumination in the image and/or perceived dress colors relate to scores on the morningness-eveningness questionnaire (a measure of chronotype). We find moderate correlations between chronotype and illumination matches (morning types giving bluer illumination matches than evening types) and chronotype and dress body matches, but these are significant only at the 10% level. Further, although inferred illumination chromaticity in the image explains variation in the color matches to the dress (confirming the color constancy hypothesis), color constancy thresholds obtained using an established illumination discrimination task are not related to dress color perception. We also find achromatic settings depend on luminance, suggesting that subjective white point differences may explain the variation in dress color perception only if settings are made at individually tailored luminance levels. The results of such achromatic settings are inconsistent with their assumed correspondence to perceived illumination. Finally, our results suggest that perception and naming are disconnected, with observers reporting different color names for the dress photograph and their isolated color matches, the latter best capturing the variation in the matches.

Interferometric gravitational wave detectors operate with high optical power in their arms in order to achieve high shot-noise limited strain sensitivity. A significant limitation to increasing the optical power is the phenomenon of three-mode parametric instabilities, in which the laser field in the arm cavities is scattered into higher-order optical modes by acoustic modes of the cavity mirrors. The optical modes can further drive the acoustic modes via radiation pressure, potentially producing an exponential buildup. One proposed technique to stabilize parametric instability is active damping of acoustic modes. We report here the first demonstration of damping a parametrically unstable mode using active feedback forces on the cavity mirror. A 15 538 Hz mode that grew exponentially with a time constant of 182 sec was damped using electrostatic actuation, with a resulting decay time constant of 23 sec. An average control force of 0.03 nN was required to maintain the acoustic mode at its minimum amplitude.

Background: The epidemic of non-communicable diseases (NCDs) in low and middle income countries (LMICs) is widely recognised as the next major challenge to global health. However, in many LMICs, infectious diseases are still prevalent resulting in a "double burden" of disease. With increased life expectancy and longevity with HIV, older adults may particularly be at risk of this double burden. Here we describe the relative contributions of infections and NCDs to hospital admissions and mortality, according to age, in Malawi's largest hospital., Methods: Primary diagnosis on discharge/death, mortality rates, and HIV status were recorded prospectively on consecutive adult medical in-patients over 2 years using an electronic medical records system. Diagnoses were classified as infections or NCDs and analysed according to age and gender., Findings: 10,191 records were analysed. Overall, infectious diseases, particularly those associated with HIV, were the leading cause of admission. However, in adults ≥55 years, NCDs were the commonest diagnoses. In adults <55 years 71% of deaths were due to infections whereas in adults ≥55 years 56% of deaths were due to NCDs., Interpretation: Infectious diseases are still the leading cause of adult admission to a central hospital in Malawi but in adults aged ≥55 years NCDs are the most frequent diagnoses. HIV was an underlying factor in the majority of adults with infections and was also present in 53% of those with NCDs. These findings highlight the need for further health sector shifts to address the double burden of infectious and NCDs, particularly in the ageing population., Competing Interests: The authors have declared that no competing interests exist.

Characterizing humans' ability to discriminate changes in illumination provides information about the visual system's representation of the distal stimulus. We have previously shown that humans are able to discriminate illumination changes and that sensitivity to such changes depends on their chromatic direction. Probing illumination discrimination further would be facilitated by the use of computer-graphics simulations, which would, in practice, enable a wider range of stimulus manipulations. There is no a priori guarantee, however, that results obtained with simulated scenes generalize to real illuminated scenes. To investigate this question, we measured illumination discrimination in real and simulated scenes that were well-matched in mean chromaticity and scene geometry. Illumination discrimination thresholds were essentially identical for the two stimulus types. As in our previous work, these thresholds varied with illumination change direction. We exploited the flexibility offered by the use of graphics simulations to investigate whether the differences across direction are preserved when the surfaces in the scene are varied. We show that varying the scene's surface ensemble in a manner that also changes mean scene chromaticity modulates the relative sensitivity to illumination changes along different chromatic directions. Thus, any characterization of sensitivity to changes in illumination must be defined relative to the set of surfaces in the scene.

This commentary discusses the recent pioneering overhaul of training for UK doctors wishing to pursue a career in the infection specialities. Changes include the introduction of new curricula that embrace increased collaboration between the laboratory-based and clinical specialties and a broad-based infection training period, named 'Combined Infection Training', which has never been seen before. Here, we discuss the benefits and challenges associated with the collaborative approach to training with particular reference to points that educators responsible for training programme design need to consider. We also describe our own local experiences in adopting a proactive, multidisciplinary approach to address potential obstacles prospectively., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Parametric instabilities have long been studied as a potentially limiting effect in high-power interferometric gravitational wave detectors. Until now, however, these instabilities have never been observed in a kilometer-scale interferometer. In this Letter, we describe the first observation of parametric instability in a gravitational wave detector, and the means by which it has been removed as a barrier to progress.

The mechanisms underlying functional mitral regurgitation (MR) and the relation between mechanism and severity of MR have not been evaluated in a large, multicenter, randomized controlled trial. Transesophageal echocardiography (TEE) was performed in 215 patients at 17 centers in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Both 2-dimensional (n = 215) and 3-dimensional (n = 81) TEEs were used to assess multiple quantitative measurements of the mechanism and severity of MR. By 2-dimensional TEE, leaflet tenting area, anterior and posterior leaflet angles, mitral annulus diameter, left ventricular (LV) end-systolic volume index, LV ejection fraction (LVEF), and sphericity index (p <0.05 for all) were significantly different across MR grades. By 3-dimensional TEE, mitral annulus area, leaflet tenting area, LV end-systolic volume index, LVEF, and sphericity index (p <0.05 for all) were significantly different across MR grades. A multivariate analysis showed a trend for annulus area (p = 0.069) and LV end-systolic volume index (p = 0.071) to predict effective regurgitant orifice area and for annulus area (p = 0.018) and LV end-systolic volume index (p = 0.073) to predict vena contracta area. In the STICH trial, multiple quantitative parameters of the mechanism of functional MR are related to MR severity. The mechanism of functional MR in ischemic cardiomyopathy is heterogeneous, but no single variable stands out as a strong predictor of quantitative severity of MR., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Currently, no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a phase 1 study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes [human adenovirus 6 (Ad6) and chimpanzee adenovirus 3 (ChAd3)]. Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cell subsets; secreted interleukin-2, interferon-γ, and tumor necrosis factor-α; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic and therapeutic vaccines for HCV.

Percutaneous mitral valve repair with the MitraClip has been shown to decrease mitral regurgitation (MR) severity, left ventricular volumes, and functional class in patients with severe (3+ or 4+) MR. Determination of which patients are optimal candidates for MitraClip therapy versus surgery has not been rigorously evaluated. Transesophageal echocardiography was prospectively performed in 113 consecutive patients referred for potential MitraClip therapy under the REALISM continued access registry. MR severity was assessed quantitatively in all patients. Mitral valve anatomy and feasibility of MitraClip placement were assessed by transesophageal echocardiography and clinical parameters. MR was degenerative (mitral valve prolapse) in 60 patients (53%), functional (anatomically normal) in 44 (39%), and thickened with restricted motion (Carpentier IIIB classification) in 9 (8%). MR was mild in 19 patients (17%), moderate in 27 (24%), and severe (3 to 4+) in 67 (59%) by Transesophageal echocardiography. MitraClip placement was performed in only 17 of 113 patients (15%); all were successful. Surgical mitral valve repair was performed in 25 patients (22%), mitral valve replacement in 12 (11%). Most patients (59 of 113, 52%) were treated medically, usually because MR was not severe enough to warrant intervention. In conclusion, most patients referred for MitraClip therapy do not have severe enough MR to warrant intervention. Of those with clinical need for intervention, surgery is more often recommended for anatomic or clinical reasons. Three-dimensional transesophageal echocardiography with quantitative assessment of MR severity is helpful in evaluating these patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In January 2010, Western University of Health Sciences launched the first phase of its Interprofessional Education (IPE) program. Our mission is to produce humanistic healthcare professionals who practice collaborative patient-centered care. The university wide comprehensive IPE program model includes didactic, experiential and clinical care phases. The first phase of the IPE program, didactic, rolled out during the 2009-2010 academic year. While the data from the first year is still being evaluated, initial indicators reveal the launching of the first year of the program was a success. Assessment is and will continue to be an essential aspect of every phase of the IPE model.

Despite continuing investigations of the efficacy of Canadian addiction treatment services and supports across a range of health care settings and socio-cultural groups, many systemic, geographic and ideological barriers to service provision for women still exist. Determining how current services and supports can become more congruent with women's gender-specific needs is a current research focus. Drawing on Butler's reformulation of Althusser's interpellation, this article explores the power of hailing, where hailing power lies, and how hailing operates in discourses about addiction that appear in women's talk of their encounters with addiction services and supports. The article briefly outlines Butler's understanding of interpellation and examines ways by which gender operates as both condition and effect in women becoming addicts. I argue that women's narratives reveal patterns of interaction that intersect and generate complex social meanings and identities, and serve to get women's attention in terms of seeing themselves as addicts. Further, I argue that powerful competing discourses concerning gender and the medicalization of addiction, hailed through these interactions, are taken up as lived realities by some women and resisted by others. Knowing how women are hailed to take up as their own, or resist, aspects of traditional and gendered discourses within addiction treatment and recovery communities can inform gender-compassionate service provision.

A stochastic background of gravitational waves is expected to arise from a superposition of a large number of unresolved gravitational-wave sources of astrophysical and cosmological origin. It should carry unique signatures from the earliest epochs in the evolution of the Universe, inaccessible to standard astrophysical observations. Direct measurements of the amplitude of this background are therefore of fundamental importance for understanding the evolution of the Universe when it was younger than one minute. Here we report limits on the amplitude of the stochastic gravitational-wave background using the data from a two-year science run of the Laser Interferometer Gravitational-wave Observatory (LIGO). Our result constrains the energy density of the stochastic gravitational-wave background normalized by the critical energy density of the Universe, in the frequency band around 100 Hz, to be <6.9 x 10(-6) at 95% confidence. The data rule out models of early Universe evolution with relatively large equation-of-state parameter, as well as cosmic (super)string models with relatively small string tension that are favoured in some string theory models. This search for the stochastic background improves on the indirect limits from Big Bang nucleosynthesis and cosmic microwave background at 100 Hz.

We report on an all-sky search with the LIGO detectors for periodic gravitational waves in the frequency range 50-1100 Hz and with the frequency's time derivative in the range -5 x 10{-9}-0 Hz s{-1}. Data from the first eight months of the fifth LIGO science run (S5) have been used in this search, which is based on a semicoherent method (PowerFlux) of summing strain power. Observing no evidence of periodic gravitational radiation, we report 95% confidence-level upper limits on radiation emitted by any unknown isolated rotating neutron stars within the search range. Strain limits below 10{-24} are obtained over a 200-Hz band, and the sensitivity improvement over previous searches increases the spatial volume sampled by an average factor of about 100 over the entire search band. For a neutron star with nominal equatorial ellipticity of 10{-6}, the search is sensitive to distances as great as 500 pc.

We present a LIGO search for short-duration gravitational waves (GWs) associated with soft gamma ray repeater (SGR) bursts. This is the first search sensitive to neutron star f modes, usually considered the most efficient GW emitting modes. We find no evidence of GWs associated with any SGR burst in a sample consisting of the 27 Dec. 2004 giant flare from SGR 1806-20 and 190 lesser events from SGR 1806-20 and SGR 1900+14. The unprecedented sensitivity of the detectors allows us to set the most stringent limits on transient GW amplitudes published to date. We find upper limit estimates on the model-dependent isotropic GW emission energies (at a nominal distance of 10 kpc) between 3x10;{45} and 9x10;{52} erg depending on waveform type, detector antenna factors and noise characteristics at the time of the burst. These upper limits are within the theoretically predicted range of some SGR models.

Purpose: To determine the effects of age on blood flow measurements obtained using the scanning laser Doppler flowmeter (SLDF)., Method: Using SLDF (Heidelberg retina flowmeter, Heidelberg Engineering, Germany) three 10 degrees images were taken of the superior temporal retina and three further images of the superior temporal neuroretinal rim in 15 young, healthy subjects (mean age 27.9 years +/- 6.2 years) and 15 mature, healthy subjects (mean age 65.2 years +/- 13.7 years). In addition, measurements were taken of the lamina cribrosa in 12 of the volunteers from each subject group (mean age 27.1 +/- 6.3 years and 64.8 +/- 13.2 years respectively). Using a 10 x 10 pixel measurement frame, blood flow readings were obtained at a predetermined position on the retina, neuroretinal rim and lamina cribrosa. Student's two-tailed unpaired t-tests were used to compare measures of blood flow, volume and velocity between the two subject groups (P < 0.05). In addition, linear regression analysis was used to assess the relationship between age and blood flow, volume and velocity at the retina, neuroretinal rim and lamina cribrosa., Results: Retinal blood volume measured at the retina was significantly lower in the mature compared with the young subject group (P = 0.01). Mature subjects also exhibited reduced blood flow and velocity at the neuroretinal rim (P = 0.01 for both parameters) and lamina cribrosa (P = 0.008 and P = 0.01 respectively). Regression analysis revealed negative trends for all blood flow parameters in each of the anatomical areas with advancing age. Significant negative correlations were obtained for retinal blood volume (r = -0.455, P < 0.05), neuroretinal rim blood velocity (r = -0.359, P < 0.05) and lamina cribrosa blood volume (r = -0.475, P < 0.05)., Conclusion: Capillary blood flow in the retina, neuroretinal rim and lamina cribrosa decreases with advancing age. This may be of consequence in the progression of chronic ocular diseases such as glaucoma, and should be considered in the longitudinal determination of change in disease monitoring.

Aims: To assess the feasibility of training nurse practitioners to perform bone marrow aspiration and trephine biopsy, and to compare the quality of these samples with those obtained by medical staff., Methods: A retrospective audit was undertaken of nurse practitioner and medical staff performance in bone marrow procedures in a busy haematology day unit., Results: Nurse practitioners fared favourably in comparison with medical staff in performing bone marrow trephine biopsies, with mean biopsy lengths of 11 mm and 10.7 mm respectively. However, only 78% of the smears obtained by the nurses were judged technically satisfactory, compared with 91% prepared by doctors. This discrepancy was thought to be due largely to the quality of slide spreading., Conclusions: With motivated staff and a structured educational and training programme it is possible for nurse practitioners to perform the techniques of bone marrow aspiration and biopsy, and obtain specimens of satisfactory quality, thus improving efficiency of the haematology day unit and increasing quality of patient care.