The red and yellow hypergiants are a rare and important phase in the evolution of the most massive stars that can reach the cool part of the HR Diagram. The hypergiant phase is commonly characterized by high, often episodic mass-loss rates and significant changes in spectral type, probably due to the formation of a pseudo photopsphere during a high mass-loss episode. Many of the yellow hypergiants are the immediate successors to the most luminous red supergiants, and often show evidence in their dusty, circumstellar envelopes from past red supergiant activity. In this paper we review the yellow and red hypergiants with an emphasis on how they differ from more normal red supergiants.

The red and yellow hypergiants are a rare and important phase in the evolution of the most massive stars that can reach the cool part of the HR Diagram. The hypergiant phase is commonly characterized by high, often episodic mass-loss rates and significant changes in spectral type, probably due to the formation of a pseudo photopsphere during a high mass-loss episode. Many of the yellow hypergiants are the immediate successors to the most luminous red supergiants, and often show evidence in their dusty, circumstellar envelopes from past red supergiant activity. In this paper we review the yellow and red hypergiants with an emphasis on how they differ from more normal red supergiants.

Quantitative molecular imaging with PET can offer insights into physiologic and pathologic processes and is widely used for studying brain disorders. The NeuroEXPLORER is a recently developed dedicated brain PET system offering high spatial resolution and high sensitivity with an extended axial length. This study evaluated the quantitative precision and accuracy of the NeuroEXPLORER with phantom and human data for a variety of imaging conditions that are relevant to dynamic neuroimaging studies. Methods: Thirty-minute scans of an image quality (IQ) phantom and a 3-dimensional Hoffman brain phantom filled with [18F]FDG were performed over 13 h, covering phantom activities of 1.3-177 MBq. Furthermore, a uniform cylindric phantom filled with 558 MBq of 11C was scanned for 4 h. Quantitative accuracy was assessed using the contrast recovery coefficient (CRC), background variability, and background bias in the IQ phantom, the recovery coefficients (RCs) in the Hoffman phantom, and the bias in the uniform phantom. Results were compared at delayed time points, with different reconstruction parameters and frame lengths down to 1 s. Moreover, randomly subsampled frames of 2 imaging time points (0-2 min and 60-90 min) from a dynamic scan of a healthy volunteer with a 177-MBq injected dose of (R)-4-(3-fluoro-5-(fluoro-18F)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidin-2-one ([18F]SynVesT-1) were used to assess quantification of brain uptake and image-derived input function extraction. Results: Negligible effects were observed on CRC and background bias with 3-177 MBq in the IQ phantom, and bias was less than 5% with 1-558 MBq in the uniform phantom. RC variations were within ±1% with 2-169 MBq in the Hoffman phantom, showcasing the system's high spatial resolution and high sensitivity. Short-frame reconstructions of the 60- to 90-min healthy-volunteer scan showed a ±1% mean difference in quantification of brain uptake for frame lengths down to 30 s and demonstrated the feasibility of measuring image-derived input function with mean absolute differences below 10% for frame lengths down to 1 s. Conclusion: The NeuroEXPLORER, with its high detection sensitivity, maintains high precision and accuracy across a wide range of imaging conditions beyond those evaluated in standard performance tests. These results demonstrate its potential for quantitative neuroimaging applications.

Blood-brain barrier (BBB) disruption is involved in the pathogenesis and progression of many neurological and systemic diseases. Non-invasive assessment of BBB permeability in humans has mainly been performed with dynamic contrast-enhanced magnetic resonance imaging, evaluating the BBB as a structural barrier. Here, we developed a novel non-invasive positron emission tomography (PET) method in humans to measure the BBB permeability of molecular radiotracers that cross the BBB through different transport mechanisms. Our method uses high-temporal resolution dynamic imaging and kinetic modeling to jointly estimate cerebral blood flow and tracer-specific BBB transport rate from a single dynamic PET scan and measure the molecular permeability-surface area (PS) product of the radiotracer. We show our method can resolve BBB PS across three PET radiotracers with greatly differing permeabilities, measure reductions in BBB PS of 18F-fluorodeoxyglucose (FDG) in healthy aging, and demonstrate a possible brain-body association between decreased FDG BBB PS in patients with metabolic dysfunction-associated steatotic liver inflammation. Our method opens new directions to efficiently study the molecular permeability of the human BBB in vivo using the large catalogue of available molecular PET tracers.

Quantitative total-body PET imaging of blood flow can be performed with freely diffusible flow radiotracers such as 15O-water and 11C-butanol, but their short half-lives necessitate close access to a cyclotron. Past efforts to measure blood flow with the widely available radiotracer 18F-fluorodeoxyglucose (FDG) were limited to tissues with high 18F-FDG extraction fraction. In this study, we developed an early-dynamic 18F-FDG PET method with high temporal resolution kinetic modeling to assess total-body blood flow based on deriving the vascular transit time of 18F-FDG and conducted a pilot comparison study against a 11C-butanol reference. Methods:The first two minutes of dynamic PET scans were reconstructed at high temporal resolution (60×1 s, 30×2 s) to resolve the rapid passage of the radiotracer through blood vessels. In contrast to existing methods that use blood-to-tissue transport rate ( K 1 ) as a surrogate of blood flow, our method directly estimates blood flow using a distributed kinetic model (adiabatic approximation to the tissue homogeneity model; AATH). To validate our 18F-FDG measurements of blood flow against a flow radiotracer, we analyzed total-body dynamic PET images of six human participants scanned with both 18F-FDG and 11C-butanol. An additional thirty-four total-body dynamic 18F-FDG PET scans of healthy participants were analyzed for comparison against literature blood flow ranges. Regional blood flow was estimated across the body and total-body parametric imaging of blood flow was conducted for visual assessment. AATH and standard compartment model fitting was compared by the Akaike Information Criterion at different temporal resolutions. Results:18F-FDG blood flow was in quantitative agreement with flow measured from 11C-butanol across same-subject regional measurements (Pearson R=0.955, p<0.001; linear regression y=0.973x-0.012), which was visually corroborated by total-body blood flow parametric imaging. Our method resolved a wide range of blood flow values across the body in broad agreement with literature ranges (e.g., healthy cohort average: 0.51±0.12 ml/min/cm3 in the cerebral cortex and 2.03±0.64 ml/min/cm3 in the lungs, respectively). High temporal resolution (1 to 2 s) was critical to enabling AATH modeling over standard compartment modeling. Conclusions:Total-body blood flow imaging was feasible using early-dynamic 18F-FDG PET with high-temporal resolution kinetic modeling. Combined with standard 18F-FDG PET methods, this method may enable efficient single-tracer flow-metabolism imaging, with numerous research and clinical applications in oncology, cardiovascular disease, pain medicine, and neuroscience.

The TORCH (Time Of internally Reflected Cherenkov light) detector is proposed for the high-luminosity Upgrade II of the LHCb experiment. The aim of TORCH is to measure time-of-flight with a 15 ps resolution per charged-particle, providing particle identification over the momentum range 2-15 GeV/c. TORCH is to be located approximately 9.5 m downstream of the LHCb interaction point, and comprises 18 modules of highly-polished 1 cm-thick quartz plates, each of 250x66cm(2). Cherenkov photons, radiated in the quartz, are focused onto an array of fast-timing micro-channel-plate detectors (MCP-PMTs) that each have a pixelation of 8 x 64 within an active area of 5.3x5.3cm(2). Test-beam studies have previously shown that a timing resolution better than 100 ps per single photon can be achieved on a half-height module. Recent advances in the development of a 16 x 96 pixelated MCP-PMT are described. A full-height module is being developed with a light-weight carbon-fibre support structure. A novel exo-skeleton jigging system is used to bond the optical elements and support each module during installation.

The TORCH detector aims to provide K/ (K/p) separation up to a momentum of about 10 (15) GeV/c by measuring their time-of-flight at the LHCb detector. Prompt Cherenkov photons are produced in a quartz radiator bar of 10 mm thickness, and propagated via total internal reflection to the periphery of the detector, where they are focused onto an array of microchannel plate photomultipliers that measure the photon arrival time and position. Pattern recognition techniques are used to compare the likelihood that the detector image is due to a given particle hypothesis. Good performance is obtained even for very high detector occupancies.

TORCH is a novel time-of-flight detector, designed to provide charged particle identification of pions, kaons and protons in the momentum range 2-20 GeV/c over a 9.5 m flight path. A detector module, comprising a 10 mm thick quartz plate, provides a source of Cherenkov photons which propagate via total internal reflection to one end of the plate. Here, the photons are focused onto an array of custom-designed Micro-Channel Plate Photo-Multiplier Tubes (MCP-PMTs) which measure their positions and arrival times. The target time resolution per photon is 70 ps which, for 30 detected photons per charged particle, results in a 10-15 ps time-of-flight resolution. A 1.25 m length TORCH prototype module employing two MCP-PMTs has been developed, and tested at the CERN PS using a charged hadron beam of 8 GeV/c momentum. The construction of the module, the properties of the MCP-PMTs and the readout electronics are described. Measurements of the collected photon yields and single-photon time resolutions have been performed as a function of particle entry points on the plate and compared to expectations. These studies show that the performance of the TORCH prototype approaches the design goals for the full-scale detector.

TORCH is a large-area and high-precision time-of-flight detector, designed to provide charged particle identification over a 2-20 GeV/c momentum range. The TORCH detector comprises a 10 mm thick quartz radiator, instrumented with photon detectors, which precisely time and measure the arrival positions of the Cherenkov photons. The photon detectors are micro-channel plate photo-multiplier tubes (MCP-PMTs) comprising a finely segmented anode of 64 x 64 anode pads, electronically ganged into 64 x 8 pixels, over a 53 x 53mm(2) area, an excellent intrinsic time resolution of similar to 30 ps, and a long lifetime of up to greater than or similar to 5 C/cm(2). The current version of the MCP-PMTs used by TORCH have been developed with an industrial partner, Photek Ltd, to satisfy the stringent requirements of the detector. The TORCH R&D programme has successfully demonstrated the detector concept through extensive laboratory and beam tests. A TORCH prototype has been constructed and has yielded encouraging results when exposed to low momentum charged hadrons. Characteristic patterns of Cherenkov photons have been recorded, illustrating the required spatial accuracy and timing resolution of 70 ps per photon. Both laboratory and beam test results are approaching the design goals of the TORCH detector.

Background and AimsInformed consent is a vital component of patient care, and should include the benefits of the procedure, as well as risks, complications and alternatives.1 As per AAGBI2 and RAUK3 standards, consent documentation for peripheral nerve blockade (PNB) is a professional and legal obligation. In response to variable documentation quality in our centre, Standardised consent labels (nicknamed the ‘Oxford sticky label’) were introduced in 2005, with regular audit and revisions, most recently May 2019.MethodsThis was the third prospective re-audit of consent documentation for PNB since the 2019 standardised label revision. On each occasion, anaesthetic charts of ~50 consecutive patients undergoing PNB were reviewed. This time the audit was not advertised to clinicians to avoid biased performance. Overall performance of documentation was assessed; use of labels was considered gold standard.ResultsStandardised labels as opposed to handwritten documentation were used in 17% of cases, declining from 28% previously. Use of labels was associated with a higher documentation quality of key information points (87% versus 23% without labels). However, the decline in label use was associated with an overall fall in frequency of key consent points being documented, to 34% from 47% previously.Overall performance has, however, improved compared with pre-label introduction.ConclusionsAppropriate documentation of valid consent is vital. Standardised labels have consistently improved this, however there is some way to go in achieving gold standard (>95%). Time pressures and lack of availability of labels often hinder comprehensive documentation, however the impending advent of electronic anaesthetic records should counter some of these issues.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies 1–3 . Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity 4,5 , its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T reg ) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T reg cells. Accordingly, in mouse models, PI3Kδi decreased the number of T reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T reg cells, accompanied by expansion of pathogenic T helper 17 (T H 17) and type 17 CD8 + T (T C 17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

The Muon g -2 Experiment at Fermilab uses a gaseous straw tracking detector to make detailed measurements of the stored muon beam profile, which are essential for the experiment to achieve its uncertainty goals. Positrons from muon decays spiral inward and pass through the tracking detector before striking an electromagnetic calorimeter. The tracking detector is therefore located inside the vacuum chamber in a region where the magnetic field is large and non-uniform. As such, the tracking detector must have a low leak rate to maintain a high-quality vacuum, must be non-magnetic so as not to perturb the magnetic field and, to minimize energy loss, must have a low radiation length. The performance of the tracking detector has met or surpassed the design requirements, with adequate electronic noise levels, an average straw hit resolution of (110 ± 20) μm, a detection efficiency of 97% or higher, and no performance degradation or signs of aging. The tracking detector's measurements result in an otherwise unachievable understanding of the muon's beam motion, particularly at early times in the experiment's measurement period when there are a significantly greater number of muons decaying. This is vital to the statistical power of the experiment, as well as facilitating the precise extraction of several systematic corrections and uncertainties. This paper describes the design, construction, testing, commissioning, and performance of the tracking detector.

TORCH is a large-area, high-precision time-of-flight (ToF) detector designed to provide charged-particle identification in the 2-20 GeV/c momentum range. Prompt Cherenkov photons emitted by charged hadrons as they traverse a 10mm quartz radiator are propagated to the periphery of the detector, where they are focused onto an array of micro-channel plate photomultiplier tubes (MCP-PMTs). The position and arrival times of the photons are used to infer the particles' time of entry in the radiator, to identify hadrons based on their ToF. The MCP-PMTs were developed with an industrial partner to satisfy the stringent requirements of the TORCH detector. The requirements include a finely segmented anode, excellent time resolution, and a long lifetime. Over an approximately 10m flight distance, the difference in ToF between a kaon and a pion with 10GeV/c momentum is 35ps, leading to a 10-15ps per track timing resolution requirement. On average 30 photons per hadron are detected, which translates to a single-photon time resolution of 70ps. The TORCH research and development program aims to demonstrate the validity of the detector concept through laboratory and beam tests, results from which are presented. A timing resolution of 70-100ps was reached in beam tests, approaching the TORCH design goal. Laboratory timing tests consist of operating the MCP-PMTs coupled to the TORCH readout electronics. A time resolution of about 50ps was measured, meeting the TORCH target timing resolution.

The red hypergiant VY CMa and the more typical red supergiant (RSG) Betelgeuse provide clear observational evidence for discrete, directed gaseous outflows in their optical and infrared imaging, spectra, and light curves. In the very luminous VY CMa, mass-loss estimates from the infrared-bright knots and clumps not only dominate its measured overall mass loss, but explain it. In the less luminous Betelgeuse, similar mass estimates of its circumstellar condensations show that they contribute significantly to its measured mass-loss rate. We present new measurements for both stars and discuss additional evidence for gaseous ejections in other RSGs. Gaseous outflows are the dominant mechanism for the most luminous RSGs and an important contributor to the more typical RSGs like Betelgeuse. We conclude that gaseous outflows, related to magnetic fields and surface activity, comparable to coronal mass ejections, are a major contributor to mass loss from RSGs and the missing component in discussions of their mass-loss mechanism.

The MMT Adaptive optics exoPlanet characterization System (MAPS) is an exoplanet characterization program that encompasses instrument development, observational science, and education. The instrument we are developing for the 6.5m MMT observatory is multi-faceted, including a refurbished 336-actuator adaptive secondary mirror (ASM); two pyramid wavefront sensors (PyWFS's); a 1-kHz adaptive optics (AO) control loop; a high-resolution and long-wavelength upgrade to the Arizona infraRed Imager and Echelle Spectrograph (ARIES); and a new-AO-optimized upgrade to the MMT-sensitive polarimeter (MMT-Pol). With the completed MAPS instrument, we will execute a 60-night science program to characterize the atmospheric composition and dynamics of ~50-100 planets around other stars. The project is approaching first light, anticipated for Summer/Fall of 2022. With the electrical and optical tests complete and passing the review milestone for the ASM’s development, it is currently being tuned. The PyWFS's are being built and integrated in their respective labs: the visible-light PyWFS at the University of Arizona (UA), and the infrared PyWFS at the University of Toronto (UT). The top-level AO control software is being developed at UA, with an on-sky calibration algorithm being developed at UT. ARIES development continues at UA, and MMT-Pol development is at the University of Minnesota. The science and education programs are in planning and preparation. We will present the design and development of the entire MAPS instrument and project, including an overview of lab results and next steps.

The Mu3e experiment aims to find or exclude the lepton flavour violating decay mu -> eee at branching fractions above 10(-16). A first phase of the experiment using an existing beamline at the Paul Scherrer Institute (PSI) is designed to reach a single event sensitivity of 2.10(-15). We present an overview of all aspects of the technical design and expected performance of the phase I Mu3e detector. The high rate of up to 10(8) muon decays per second and the low momenta of the decay electrons and positrons pose a unique set of challenges, which we tackle using an ultra thin tracking detector based on high-voltage monolithic active pixel sensors combined with scintillating fibres and tiles for precise timing measurements.

Imaging and spectroscopy of the knots, clumps, and extended arcs in the complex ejecta of VY CMa confirm a record of high mass-loss events over the past few hundred years. Hubble Space Telescope/Space Telescope Imaging Spectrograph spectroscopy of numerous small knots close to the star allow us to measure their radial velocities from the strong K i emission and determine their separate motions, spatial orientations, and time since ejecta. Their ages concentrate around 70, 120, 200, and 250 yr ago. A K i emission knot only 50 mas from the star ejected as recently as 1985–1995 may coincide with an H 2 O maser. Comparison with VY CMa’s historic light curve from 1800 to the present shows several knots with ejection times that correspond with extended periods of variability and deep minima. The similarity of this correspondence in VY CMa with the remarkable recent dimming of Betelgeuse and an outflow of gas is apparent. The evidence for similar outflows from the surface of a more typical red supergiant suggests that discrete ejections are more common and surface or convective activity is a major source of mass loss for red supergiants.

Peatland reservoirs are global hotspots for drinking water provision and are likely to become more important as demand per capita rises and the climate changes. Dissolved organic carbon (DOC) is associated with harmful disinfection byproducts and reduced aesthetic quality, and its removal is the major treatment cost. Littoral zones are known to be disproportionately important for DOC production through macrophyte inputs, and such communities are predicted to expand with warming in northern regions. However, little is known about autochthonous DOC contributions and their response to climatic change. Here we exposed mesocosms to elevated CO 2 (eCO 2 ), warming and a combined treatment across a trophic gradient. Regression analysis indicated that while sediments, macrophytes, and phytoplankton are important DOC sources ( P < 0.05), benthic algal biomass showed the strongest relationship with DOC ( P < 0.05), suggesting it is an underestimated source. DOC removal indicators, namely phenol oxidase (depolymerization) and respiration (mineralization) were inversely related to DOC concentration in oligohumic ( P < 0.05) and oligotrophic ( P < 0.1) systems, suggesting heterotrophic processes are important in DOC removal. DOC concentrations increased across all systems ( P < 0.05), irrespective of trophic status, due to increased photoautotrophic inputs (macrophyte, pelagic, and benthic algae) under eCO 2 , warming, and combined scenarios, with inhibited depolymerization and mineralization under eCO 2 , even when combined with warming ( P < 0.05 and P < 0.05 excepting the oligo‐mesotrophic reservoir P < 0.1 respectively). Increased DOC loads of all fractions, regardless of provenance, are predicted in a future climate and, thus, investment in techniques to remove a greater range of DOC fractions is proposed to help “future proof” drinking water supplies.