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Given that cancer mortality is usually a result of late diagnosis, efforts in the field of early detection are paramount to reducing cancer-related deaths and improving patient outcomes. Increasing evidence indicates that metastasis is an early event in patients with aggressive cancers, often occurring even before primary lesions are clinically detectable. Metastases are usually formed from cancer cells that spread to distant non-malignant tissues via the blood circulation, termed circulating tumour cells (CTCs). CTCs have been detected in patients with early stage cancers and, owing to their association with metastasis, might indicate the presence of aggressive disease, thus providing a possible means to expedite diagnosis and treatment initiation for such patients while avoiding overdiagnosis and overtreatment of those with slow-growing, indolent tumours. The utility of CTCs as an early diagnostic tool has been investigated, although further improvements in the efficiency of CTC detection are required. In this Perspective, we discuss the clinical significance of early haematogenous dissemination of cancer cells, the potential of CTCs to facilitate early detection of clinically relevant cancers, and the technological advances that might improve CTC capture and, thus, diagnostic performance in this setting.The authors of this Perspective propose that, with further improvement in detection efficiency, circulating tumour cells (CTCs), which are released early during cancer development, have the potential to be used for the early detection of clinically relevant, aggressive cancers. Thus, use of CTCs as diagnostic biomarkers might improve outcomes by enabling the identification of cancers at a stage at which they are more amenable to treatment while avoiding overtreatment of patients with indolent tumours.

A COVID-19 hospital guideline was implemented across all 18 acute hospitals in Wales in March 2020, promoting ward management of COVID pneumonitis and data collected across the first 3 Waves of the pandemic (Wave 1 March 1st 2020 to November 1st 2020, Wave 2 November 2st 2020 to February 21st 2021 and Wave 3 June 1st 2021 to December 14th 2021). The aim of this paper is to compare outcomes for patients by admission setting and type of ventilatory support given, with a particular focus on CPAP therapy. This is a retrospective observational study of those aged over 18 admitted to hospital with community acquired COVID-19 between March 2020 and December 2021. The outcome of interest was in-hospital mortality. Univariate logistic regression models were used to compare crude outcomes across the waves. Multivariable logistic regression models were used to assess outcomes by different settings and treatments after adjusting for Wave, age, sex, co-morbidity and deprivation. Of the 7,803 records collected, 5,887 (75.4%) met the inclusion criteria. Analysis of those cases identified statistically significant outcome improvements across the waves for all patients combined (Waves 1 to 3: 31.5% to 18.8%, p<0.01), all ward patients (28.9% to 17.7%, p<0.01), and all ICU patients (44.3% to 32.2%, p = 0.03). Sub group analyses identified outcome improvements in ward patients without any oxygen therapy (Waves 1 to 3: 22.2% to 12.7%, p<0.01), with oxygen therapy only (34.0% to 12.9%, p<0.01) and with CPAP only (63.5% to 39.2%, p<0.01). The outcome improvements for ICU patients receiving CPAP only (35.7% to 24.6%, p = 0.31) or invasive ventilation (61.6% to 54.6%, p = 0.43) were not statistically significant though the numbers being admitted to ICU were small. The logistic regression models identified important age and comorbidity effects on outcomes. The multivariable model that took these into account suggested no statistically significantly greater risk of death for those receiving CPAP on the ward compared to those receiving CPAP in ICU (OR 0.89, 95% CI: 0.49 to 1.60). There were successive reductions in mortality in inpatients over the three Waves reflecting new treatments and better management of complications. Mortality for those requiring CPAP was similar in respiratory wards and ICUs after adjusting for differences in their respective patient populations.

When pathogens become airborne, they travel associated with particles of different size and composition. Particle size determines the distance across which pathogens can be transported, as well as the site of deposition and the survivability of the pathogen. Despite the importance of this information, the size distribution of particles bearing viruses emitted by infectious animals remains unknown. In this study we characterized the concentration and size distribution of inhalable particles that transport influenza A virus (IAV), porcine reproductive and respiratory syndrome virus (PRRSV), and porcine epidemic diarrhea virus (PEDV) generated by acutely infected pigs and assessed virus viability for each particle size range. Aerosols from experimentally infected pigs were sampled for 24 days using an Andersen cascade impactor able to separate particles by size (ranging from 0.4 to 10 micrometer (μm) in diameter). Air samples collected for the first 9, 20 and the last 3 days of the study were analyzed for IAV, PRRSV and PEDV, respectively, using quantitative reverse transcription polymerase chain reaction (RT-PCR) and quantified as geometric mean copies/m(3) within each size range. IAV was detected in all particle size ranges in quantities ranging from 5.5x10(2) (in particles ranging from 1.1 to 2.1 μm) to 4.3x10(5) RNA copies/m(3) in the largest particles (9.0-10.0 μm). PRRSV was detected in all size ranges except particles between 0.7 and 2.1 μm in quantities ranging from 6x10(2) (0.4-0.7 μm) to 5.1x10(4) RNA copies/m(3) (9.0-10.0 μm). PEDV, an enteric virus, was detected in all particle sizes and in higher quantities than IAV and PRRSV (p < 0.0001) ranging from 1.3x10(6) (0.4-0.7 μm) to 3.5x10(8) RNA copies/m(3) (9.0-10.0 μm). Infectious status was demonstrated for the 3 viruses, and in the case of IAV and PRRSV, viruses were isolated from particles larger than 2.1 μm. In summary, our results indicated that airborne PEDV, IAV and PRRSV can be found in a wide range of particle sizes. However, virus viability is particle size dependent.

Digital technologies have been transforming methods of health care delivery and have been embraced within the health, social, and public response to the COVID-19 pandemic. However, this has directed attention to the “inverse information law” (also called “digital inverse care law”) and digital inequalities, as people who are most in need of support (in particular, older people and those experiencing social deprivation) are often least likely to engage with digital platforms. The response to the COVID-19 pandemic represents a sustained shift to the adoption of digital approaches to working and engaging with populations, which will continue beyond the COVID-19 pandemic. Therefore, it is important to understand the underlying factors contributing to digital inequalities and act immediately to avoid digital inequality contributing to health inequalities in the future. The response to COVID-19 represents a sustained shift to adopting digital approaches to working and engaging with populations which will continue beyond this pandemic. Therefore it is important that we understand the underlying factors contributing to digital inequalities, and act now to protect against digital inequality contributing to health inequalities in the future.

Streptococcus pyogenes (Group A Streptococcus; GAS) is exquisitely adapted to the human host, resulting in asymptomatic infection, pharyngitis, pyoderma, scarlet fever or invasive diseases, with potential for triggering post-infection immune sequelae. GAS deploys a range of virulence determinants to allow colonization, dissemination within the host and transmission, disrupting both innate and adaptive immune responses to infection. Fluctuating global GAS epidemiology is characterized by the emergence of new GAS clones, often associated with the acquisition of new virulence or antimicrobial determinants that are better adapted to the infection niche or averting host immunity. The recent identification of clinical GAS isolates with reduced penicillin sensitivity and increasing macrolide resistance threatens both frontline and penicillin-adjunctive antibiotic treatment. The World Health Organization (WHO) has developed a GAS research and technology road map and has outlined preferred vaccine characteristics, stimulating renewed interest in the development of safe and effective GAS vaccines.In this Review, Brouwer et al. summarize recent developments in our understanding of Group A Streptococcus (GAS), focusing on the epidemiologic and clinical features of GAS infection and the molecular mechanisms associated with GAS virulence and drug resistance.

The effects of climate change on biodiversity should depend in part on climate displacement rate (climate-change velocity) and its interaction with species' capacity to migrate. We estimated Late Quaternary glacial-interglacial climate-change velocity by integrating macroclimatic shifts since the Last Glacial Maximum with topoclimatic gradients. Globally, areas with high velocities were associated with marked absences of small-ranged amphibians, mammals, and birds. The association between endemism and velocity was weakest in the highly vagile birds and strongest in the weakly dispersing amphibians, linking dispersal ability to extinction risk due to climate change. High velocity was also associated with low endemism at regional scales, especially in wet and aseasonal regions. Overall, we show that low-velocity areas are essential refuges for Earth's many small-ranged species.

γ-aminobutyric acid-mediated (GABAergic) inhibition plays a critical role in shaping neuronal activity in the neocortex. Numerous experimental investigations have examined perisomatic inhibitory synapses, which control action potential output from pyramidal neurons. However, most inhibitory synapses in the neocortex are formed onto pyramidal cell dendrites, where theoretical studies suggest they may focally regulate cellular activity. The precision of GABAergic control over dendritic electrical and biochemical signaling is unknown. By using cell type-specific optical stimulation in combination with two-photon calcium (Ca²⁺) imaging, we show that somatostatin-expressing interneurons exert compartmentalized control over postsynaptic Ca²⁺ signals within individual dendritic spines. This highly focal inhibitory action is mediated by a subset of GABAergic synapses that directly target spine heads. GABAergic inhibition thus participates in localized control of dendritic electrical and biochemical signaling.

Results of the commissioning of the first Gemini Multi‐Object Spectrograph (GMOS) are described. GMOS and the Gemini–North telescope act as a complete system to exploit a large 8 m aperture with improved image quality. Key GMOS design features such as the on‐instrument wave‐front sensor (OIWFS) and active flexure compensation system maintain very high image quality and stability, allowing precision observations of many targets simultaneously while reducing the need for frequent recalibration and reacquisition of targets. In this paper, example observations in imaging, long‐slit, and multiobject spectroscopic modes are presented and verified by comparison with data from the literature. The expected high throughput of GMOS is confirmed from standard star observations; it peaks at about 60% when imaging in the \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $r^{\\prime }$ \\end{document} and \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $i^{\\prime }$ \\end{document} bands, and at 45%–50% in spectroscopic mode at 6300 Å. Deep GMOS photometry in the \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $g^{\\prime }$ \\end{document} , \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $r^{\\prime }$ \\end{document} , and \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $i^{\\prime }$ \\end{document} filters is compared to data from the literature, and the uniformity of this photometry across the GMOS field is verified. The multiobject spectroscopic mode is demonstrated by observations of the galaxy cluster A383. Centering of objects in the multislit mask was achieved to an rms accuracy of 80 mas across the 5 \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $\\farcm$\\end{document} 5 field, and an optimized setup procedure (now in regular use) improves this to better than 50 mas. Stability during these observations was high, as expected: the average shift between object and slit positions was 5.3 mas hr−1, and the wavelength scale drifted by only 0.1 Å hr−1(in a setup with spectral resolution of 6 Å). Finally, the current status of GMOS on Gemini–North is summarized, and future plans are outlined.

ObjectivesTo measure work-related burnout in all groups of health service staff during the COVID-19 pandemic and to identify factors associated with work-related burnout.DesignCross-sectional staff survey.SettingAll staff grades and types across primary and secondary care in a single National Health Service organisation.Participants257 staff members completed the survey, 251 had a work-related burnout score and 239 records were used in the regression analysis.Primary and secondary outcome measures(1) Work-related burnout as measured by the Copenhagen Burnout Inventory; (2) factors associated with work-related burnout identified through a multiple linear regression model; and (3) factors associated with work-related burnout identified through thematic analysis of free text responses.ResultsAfter adjusting for other covariates (including age, sex, job, being able to take breaks and COVID-19 knowledge), we observed meaningful changes in work-related burnout associated with having different COVID-19 roles (p=0.03), differences in the ability to rest and recover during breaks (p<0.01) and having personal protective equipment concerns (p=0.04). Thematic analysis of the free text comments also linked burnout to changes in workload and responsibility and to a lack of control through redeployment and working patterns. Reduction in non-COVID-19 services has resulted in some members of staff feeling underutilised, with feelings of inequality in workload.ConclusionsOur analyses support anecdotal reports of staff struggling with the additional pressures brought on by COVID-19. All three of the factors we found to be associated with work-related burnout are modifiable and hence their effects can be mitigated. When we next find ourselves in extraordinary times the ordinary considerations of rest and protection and monitoring of the impact of new roles will be more important than ever.

The broadening of atomic emission lines by high-velocity motion of gas near accreting supermassive black holes is an observational hallmark of quasars 1 . Observations of broad emission lines could potentially constrain the mechanism for transporting gas inwards through accretion disks or outwards through winds 2 . The size of regions for which broad emission lines are observed (broad-line regions) has been estimated by measuring the delay in light travel time between the variable brightness of the accretion disk  continuum and the emission lines 3 —a method known as reverberation mapping. In some models the emission lines arise from a continuous outflow 4 , whereas in others they arise from orbiting gas clouds 5 . Directly imaging such regions has not hitherto been possible because of their small angular size (less than 10 −4 arcseconds 3 , 6 ). Here we report a spatial offset (with a spatial resolution of 10 −5 arcseconds, or about 0.03 parsecs for a distance of 550 million parsecs) between the red and blue photo-centres of the broad Paschen-α line of the quasar 3C 273 perpendicular to the direction of its radio jet. This spatial offset corresponds to a gradient in the velocity of the gas and thus implies that the gas is orbiting the central supermassive black hole. The data are well fitted by a broad-line-region model of a thick disk of gravitationally bound material orbiting a black hole of 3 × 10 8 solar masses. We infer a disk radius of 150 light days; a radius of 100–400 light days was found previously using reverberation mapping 7 – 9 . The rotation axis of the disk aligns in inclination and position angle with the radio jet. Our results support the methods that are often used to estimate the masses of accreting supermassive black holes and to study their evolution over cosmic time. High-angular-resolution observations of the quasar 3C 273 reveal that it has a relatively small but thick disk, viewed nearly face-on, in which material is orbiting the central supermassive black hole.