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Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient’s cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment., Tracking tumour evolution in a patient via circulating tumour DNA (ctDNA) is complicated due to the unknown mix of fragmented alleles from different cancer lesions. Here, the authors make use of a rapid autopsy program to demonstrate how representative ctDNA profiling is of metastasis, as well as presenting methylation profiling method to track evolutionary change.

Background - Involvement of internal mammary lymph nodes (IMLN) in early breast cancer (EBC) leads to an upstaging of the disease anatomically. Unrecognized involvement of IMLNs leading to under-staging and under-treatment has been a hypothesis of studies demonstrating worse outcomes for medial tumours. Since surgery for removal of IMLNs is associated with high morbidity and radical surgical excision does not improve survival, surgical excision of IMLNs is not part of routine EBC treatment. Recent NCCN guidelines recommend IMLN irradiation for high risk EBC patients to reduce mortality. Metastasis to IMLNs may have a different impact on prognosis and management according to whether detected at the time of primary diagnosis, or later. Aims - The primary aim was to document the incidence of IMLN involvement in an EBC cohort - who underwent autologous deep inferior epigastric perforator (DIEP) flap reconstruction with unplanned sampling of 1 or more IMLNs - to ascertain the incidence of IMLN involvement. Our secondary aim was to ascertain whether IMLN involvement had an impact on management and/or prognosis. Materials and methods -We analyzed retrospectively collected data from a prospectively maintained database of patients who underwent DIEP flap reconstruction at the Royal Marsden Hospital, from April 2006 to March 2018. We used Freeman - Halton extension for Fisher’s test to assess association of IMN involvement with overall survival. Results - Of the 1471 women who underwent free flap reconstruction (1729 flaps) during this time period, 300 with EBC had their IMLNs sampled at the time of DIEP surgery. Of these, 36 had metastasis to their IMLN (incidence of 12%). The median age was 47 years and mean follow up was 34.5 months. Based on timing from initial diagnosis, 17 women had immediate DIEP flap reconstruction, 9 had delayed reconstruction (mean time from primary surgery 25 months) and 10 had reconstruction after mastectomy for loco-regional recurrence (7 at time of mastectomy for recurrence, 3 delayed). We compared outcomes for these 3 groups. Of these 36 patients, 19 had no preoperative staging and were staged only after they were found to have involved IMLNs. Four (2 in the delayed and 2 in the reconstruction after local recurrence group) of these 19 were found to have more widespread metastatic disease. Apart from these 4, based on IMLN involvement, treatment was altered in 17 others (total 21/36, 58.3%) - 8/17 in the immediate group, 7/9 in the delayed group and 2/8 for DIEP after local recurrence. The commonest alteration in treatment was addition of IMLN chain RT in 7 followed by change in endocrine therapy in 5; three had both. One patient who underwent immediate reconstruction had a negative SLN and had systemic adjuvant chemotherapy based solely on the involved IMLN. At a median follow up of 14 months, 12 patients (all either delayed or after local recurrence) of 19 relapsed with metastatic disease and 8 of them died due to disease progression. The local recurrence group had the highest rate of cancer-related mortality (p value < 0.0001) Conclusion - IMLN involvement leads to upstaging of the disease resulting in more significant change in treatment in those undergoing delayed autologous reconstruction. Local recurrence carries the worst prognosis. Staging prior to delayed DIEP surgery purely for reconstruction should be based on risk (from primary diagnosis) and all patients planned for DIEP reconstruction after local recurrence should undergo appropriate pre-operative staging investigations. Multivariate survival analysis using Cox’ proportional hazards model for those with involved versus uninvolved IMLNs to ascertain their prognostic significance will also be reported. Citation Format: Pooja Padmanabhan, Tania Policastro, Natalie To, Jennifer E Rusby, Stuart E James, Paul A Harris, Peter A Barry. The relevance of internal mammary lymph nodes found during autologous breast reconstruction [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-44.

Frequency-domain multiplexing is a readout technique for transition edge sensor bolometer arrays used on modern CMB experiments, including the SPT-3G receiver. Here, we present design details and performance measurements for a low-parasitic frequency-domain multiplexing readout. Reducing the parasitic impedance of the connections between cryogenic components provides a path to improving both the crosstalk and noise performance of the readout. Reduced crosstalk will in turn allow higher multiplexing factors. We have demonstrated a factor of two improvement in parasitic resistance compared to SPT-3G hardware. Reduced parasitics also permits operation of lower-resistance bolometers, which enables better optimization of R$_{\rm{bolo}}$ for improved readout noise performance. The prototype system exhibits noise performance comparable to SPT-3G readout hardware when operating SPT-3G detectors., Comment: 7 pages, 4 figures. Submitted to J. Low Temp. Detectors

Future cosmic microwave background (CMB) experiments, including the large scale ground-based Stage Four CMB Experiment (CMB-S4), satellites, and balloons, aim to map the CMB to an unprecedented precision in order to answer several key questions in cosmology. However, to reach the target noise sensitivity, more than 100,000 detectors will be needed. Arrays of kinetic inductance detectors (KIDs) are a promising alternative for experiments that require large number of detectors due to the intrinsic multiplexing capabilities. We present the fabrication procedure for a prototype planar orthomode transducer (OMT)-coupled multi-color KID array optimized for 220/270 GHz frequency bands. These devices are made from silicon-on-insulator wafers to provide a low-loss substrate for the KIDs. The OMT couples the two polarizations of light from a wide-band feedhorn to separate Nb/SiN/Nb microstrip lines, which are then coupled to Al/Nb lumped-element KIDs (LEKIDs). The silicon on the backside of the OMT is etched away using deep reactive ion etch to release the OMT membrane to enable operation over a wide bandwidth. Finally, the buried oxide is removed underneath the KID capacitors in order to minimize two-level system noise and loss mitigation. We achieved a good yield (> 80%) on our prototype devices.

The migration of hydrocarbons from source-rock to reservoir is a critical stage in petroleum system evolution. However, as migration occurs along confined pathways over geologically rapid timescales it is challenging to place quantitative constraints on migration behaviour in terms of interaction with other basinal fluids, flux, and lengthscales associated with this process. Due to their inert nature, noble gases are ideal tracers of fluid provenance and physical processes in a variety of subsurface systems, and thus can serve as a potential geochemical indicator of migration distance. The recent proliferation of unconventional hydrocarbon production (i.e., production directly from source-rocks) allows for the analysis of fluids from these strata. Here we present noble gas data from natural gas samples produced from 27 related conventional and unconventional wells within the East Texas basin. These data enable characterisation of fluids during migration from source-rock to conventional reservoir. Unconventional gases and fluids are produced from the Haynesville shale (n = 8), and conventional gases and fluids are sourced from the overlying Cotton Valley (n = 5), Travis Peak (n = 9), and James Lime (n = 5) formations. Samples consist primarily of methane (>70%), with small contributions from longer-chain hydrocarbons, and other gases including CO2 and N2. Atmosphere-derived 36Ar, which is introduced into natural gas accumulations via interaction with groundwater during hydrocarbon generation and migration, is consistently higher in samples that have undergone a greater migration distance from the source interval. Thus, calculated volume ratios of gas-water interaction (Vg/Vw) show a far greater incidence of groundwater interaction in migrated samples. Radiogenically-produced 40Ar is also consistently elevated in migrated samples, despite these reservoirs being located in geologically younger strata. We derive the representative volume of rock required to produce the observed radiogenic 40Ar in each sample and show that samples that have migrated further have acquired radiogenic isotopes from larger volumes of rock. Furthermore, our volumetric parameters derived from atmospheric and radiogenic isotopes are consistent with a simple conceptual model of migration. We quantitatively apply this model to demonstrate that migration occurs along relatively localised pathways. Helium (3He/4He) and argon (40Ar/36Ar) isotopes are correlated and show elevated amounts of mantle-derived 3He and radiogenic 40Ar in migrated samples. We interpret this to represent mixing between a pristine source-rock signature and an endmember characterised by elevated 3He/4He and 40Ar/36Ar, likely representative of mantle-enriched groundwater circulating in the wider hydrogeological basin. Finally, we use an advection-diffusion model to show that enriched mantle 3He in the shallower strata and towards the southern edge of the basin can be explained by influx of mantle helium along the fault-bounded southern edge of the basin over timescales of millions of years. Together these approaches represent the first complete noble gas based characterization of a hydrocarbon system, sampling migration from source-rock to trap. We show conclusively that both atmospheric and radiogenic noble gases are entrained in the hydrocarbon phase during migration and that concentrations scale proportionally with migration distance, as greater volumes of groundwater and host rock are encountered.

Rhesus cytomegalovirus (RhCMV) infection of rhesus macaques (Macaca mulatta) is a valuable nonhuman primate model of human CMV (HCMV) persistence and pathogenesis. In vivo studies predominantly use tissue culture-adapted variants of RhCMV that contain multiple genetic mutations compared to wild-type (WT) RhCMV. In many studies, animals have been inoculated by non-natural routes (e.g., subcutaneous, intravenous) that do not recapitulate disease progression via the normative route of mucosal exposure. Accordingly, the natural history of RhCMV would be more accurately reproduced by infecting macaques with strains of RhCMV that reflect the WT genome using natural routes of mucosal transmission. Herein, we tested two WT-like RhCMV strains, UCD52 and UCD59, and demonstrated that systemic infection and frequent, high-titer viral shedding in bodily fluids occurred following oral inoculation. RhCMV disseminated to a broad range of tissues, including the central nervous system and reproductive organs. Commonly infected tissues included the thymus, spleen, lymph nodes, kidneys, bladder, and salivary glands. Histological examination revealed prominent nodular hyperplasia in spleens and variable levels of lymphoid lymphofollicular hyperplasia in lymph nodes. One of six inoculated animals had limited viral dissemination and shedding, with commensurately weak antibody responses to RhCMV antigens. These data suggest that long-term RhCMV infection parameters might be restricted by local innate factors and/or de novo host immune responses in a minority of primary infections. Together, we have established an oral RhCMV infection model that mimics natural HCMV infection. The virological and immunological parameters characterized in this study will greatly inform HCMV vaccine designs for human immunization. IMPORTANCE Human cytomegalovirus (HCMV) is globally ubiquitous with high seroprevalence rates in all communities. HCMV infections can occur vertically following mother-to-fetus transmission across the placenta and horizontally following shedding of virus in bodily fluids in HCMV infected hosts and subsequent exposure of susceptible individuals to virus-laden fluids. Intrauterine HCMV has long been recognized as an infectious threat to fetal growth and development. Since vertical HCMV infections occur following horizontal HCMV transmission to the pregnant mother, the nonhuman primate model of HCMV pathogenesis was used to characterize the virological and immunological parameters of infection following primary mucosal exposures to rhesus cytomegalovirus.

We demonstrate microwave-mediated distant magnon-magnon coupling on a superconducting circuit platform, incorporating chip-mounted single-crystal Y$_3$Fe$_5$O$_{12}$ (YIG) spheres. Coherent level repulsion and dissipative level attraction between the magnon modes of the two YIG spheres are demonstrated. The former is mediated by cavity photons of a superconducting resonator, and the latter is mediated by propagating photons of a coplanar waveguide. Our results open new avenues towards exploring integrated hybrid magnonic networks for coherent information processing on a quantum-compatible superconducting platform., Comment: 6 pages, 4 figures, Accepted in Phys. Rev. Lett

Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and no human models exist at present. We harvested ALNs from ten BC patients, and perfused them at 37 °C ex vivo for up to 24 h. Controlled autologous testing showed that ALNs remain viable after 24 h of ex vivo perfusion: haematoxylin and eosin‐stained histological appearance and proliferation (by Ki67 immunohistochemistry) did not change significantly over time for any perfused ALN compared with a control from time‐point zero. Furthermore, targeted gene expression analysis (NanoString PanCancer IO360 panel) showed that only 21/750 genes were differentially expressed between control and perfused ALNs (|log2 FC| > 1 and q

Frequency-domain multiplexing (fMux) is an established technique for the readout of large arrays of transition edge sensor (TES) bolometers. Each TES in a multiplexing module has a unique AC voltage bias that is selected by a resonant filter. This scheme enables the operation and readout of multiple bolometers on a single pair of wires, reducing thermal loading onto sub-Kelvin stages. The current receiver on the South Pole Telescope, SPT-3G, uses a 68x fMux system to operate its large-format camera of $\sim$16,000 TES bolometers. We present here the successful implementation and performance of the SPT-3G readout as measured on-sky. Characterization of the noise reveals a median pair-differenced 1/f knee frequency of 33 mHz, indicating that low-frequency noise in the readout will not limit SPT-3G's measurements of sky power on large angular scales. Measurements also show that the median readout white noise level in each of the SPT-3G observing bands is below the expectation for photon noise, demonstrating that SPT-3G is operating in the photon-noise-dominated regime., Comment: 9 pages, 5 figures submitted to the Journal of Low Temperature Physics: LTD18 Special Edition

The development of a vaccine to prevent congenital human cytomegalovirus (HCMV) disease is a public health priority. We tested rhesus CMV (RhCMV) prototypes of HCMV vaccine candidates in a seronegative macaque oral challenge model. Immunogens included a recombinant pentameric complex (PC; gH/gL/pUL128/pUL130/pUL131A), a postfusion gB ectodomain, and a DNA plasmid that encodes pp65-2. Immunization with QS21-adjuvanted PC alone or with the other immunogens elicited neutralizing titers comparable to those elicited by RhCMV infection. Similarly, immunization with all 3 immunogens elicited pp65-specific cytotoxic T-cell responses comparable to those elicited by RhCMV infection. RhCMV readily infected immunized animals and was detected in saliva, blood, and urine after challenge in quantities similar to those in placebo-immunized animals. If HCMV evades vaccine-elicited immunity in humans as RhCMV evaded immunity in macaques, a HCMV vaccine must elicit immunity superior to, or different from, that elicited by the prototype RhCMV vaccine to block horizontal transmission.

Noble gases record fluid interactions in multiphase subsurface environments through fractionation processes during fluid equilibration. Water in the presence of hydrocarbons at the subsurface acquires a distinct elemental signature due to the difference in solubility between these two fluids. We find the atmospheric noble gas signature in produced water is partially preserved after hydrocarbons production and water disposal to unlined ponds at the surface. This signature is distinct from meteoric water and can be used to trace oil-field water seepage into groundwater aquifers. We analyse groundwater (n = 30) and fluid disposal pond (n = 2) samples from areas overlying or adjacent to the Fruitvale, Lost Hills, and South Belridge Oil Fields in the San Joaquin Basin, California, USA. Methane (2.8 × 10−7 to 3 × 10−2 cm3 STP/cm3) was detected in 27 of 30 groundwater samples. Using atmospheric noble gas signatures, the presence of oil-field water was identified in 3 samples, which had equilibrated with thermogenic hydrocarbons in the reservoir. Two (of the three) samples also had a shallow microbial methane component, acquired when produced water was deposited in a disposal pond at the surface. An additional 6 samples contained benzene and toluene, indicative of interaction with oil-field water; however, the noble gas signatures of these samples are not anomalous. Based on low tritium and 14C contents (≤ 0.3 TU and 0.87–6.9 pcm, respectively), the source of oil-field water is likely deep, which could include both anthropogenic and natural processes. Incorporating noble gas analytical techniques into the groundwater monitoring programme allows us to 1) differentiate between thermogenic and microbial hydrocarbon gas sources in instances when methane isotope data are unavailable, 2) identify the carrier phase of oil-field constituents in the aquifer (gas, oil-field water, or a combination), and 3) differentiate between leakage from a surface source (disposal ponds) and from the hydrocarbon reservoir (either along natural or anthropogenic pathways such as faulty wells).

Herpesvirus-based vectors are attractive for use both as conventional and as transmissible vaccines against emerging zoonoses in hard-to-reach animal populations. However, the threat of off-site mutations during genetic manipulation of vector genomes poses a significant challenge to vaccine construction. Herein, we present the HHi-FiVe (herpesvirus high-fidelity vector) construction pipeline for generating herpesvirus-based vectors by modifying bacterial artificial chromosomes (BACs) and monitoring integrity at each stage by complete genome sequencing. We used this pipeline to repair a highly mutated rhesus cytomegalovirus BAC containing an Ebola virus transgene. The vector derived from this BAC had been shown previously to protect rhesus macaques from lethal Ebola virus challenge by conventional vaccination. Repair of this BAC restored wild-type cellular tropism to the vector, which is essential for transmissible vaccination. Construction of this candidate transmissible vaccine against Ebola virus demonstrates the utility of the HHi-FiVe pipeline for creating precision-made herpesvirus-based vectors.

Volatile elements are concentrated at Earth's surface, forming a rich atmosphere and oceans which enabled the eventual emergence of life. However, volatiles are also abundant in solid Earth reservoirs, such as the crust and mantle, and these reservoirs play a key role in moderating volatile movement throughout the planet. Continental cratons represent a potentially large, yet under-constrained volatile reservoir. When cratonic regions are catastrophically disrupted by large volcanic and/or rifting events, they release massive amounts of volatiles into Earth's atmosphere on geologically-abrupt timescales (e.g., Lowenstern et al., 2014 ; Muirhead et al., 2020 ). Here, we report gas data (He-Ne-N2-Ar-CO2) from seeps along the flanks of the Tanzanian craton, within the western branch of the East African Rift System (EARS) - a region where the stable continental craton is actively being broken apart by rifting and simultaneously heated by plume-induced volcanism. Bulk gas and noble gas isotopic data are reported in seeps from three regions: 1) the Rukwa Rift Basin (RRB), 2) the Lupa Hydrothermal System (LHS) and 3) the Rungwe Volcanic Province (RVP). Seep gases from the RRB are dominantly comprised of N2 and He, with >90% N2 concentrations, high 4He concentrations (2.4–6.9%) and radiogenic He isotopes (0.16–0.20 RA). Seeps in the LHS - located between RRB and RVP - are characterized by little-to-no N2, high CO2 contents (72–84%), relatively low He contents (0.008–0.15%), and higher 3He/4He (0.95–0.99 RA). RVP gases have high CO2 (78%) and low 4He (0.0003%) and more mantle-like He isotopes (3.27–4.00 RA) consistent with previous findings ( Pik et al., 2006 ; Barry et al., 2013 ). All neon isotopes can be explained by mixing between air, high O/F crust and depleted Mid Oceanic Ridge Basalt (MORB) mantle-like signatures. RVP neon isotope seep data potentially suggest a solar-like deep mantle contribution, consistent with findings in rocks from the area ( Halldorsson et al., 2014 ), however we note that this signal is difficult to discern from mass dependent fractionation (MDF). The largest 40Ar/36Ar anomalies occur in RRB, with resolvable excess 40Ar derived from radiogenic production in the crust. Using a noble gas solubility model, we calculate volumetric gas to water ratios (Vg/Vw) and show that Vg/Vw values are low for RRB (0.1), consistent with longer migration distances, whereas Vg/Vw are higher for LHS (Vg/Vw = 0.1–10) and RVP (Vg/Vw = 3–12), suggesting a more direct conduit for volatiles from source to surface. In summary, these data demonstrate interaction between two distinct helium sources, one of which is crustal in origin (most prominent in RRB) and the other being mantle-derived (enriched in RVP). The extent of mixing between the two is shown to be influenced by proximity to rift-related fault structures, groundwater interaction and magmatic heat.

The purpose of this review is to describe on-going and upcoming real-world studies that will aid the cystic fibrosis (CF) community in understanding the long-term efficacy, safety and challenges in utilizing this therapy and managing care.The triple combination of elexacaftor, tezacaftor and ivacaftor (ETI) has been demonstrated to improve lung function, weight and quality of life in children and adults with CF with at least one copy of Phe508del. Treatment with ETI will potentially be available for approximately 90% of the CF population and change the face of CF.In spite of early demonstrations of short-term efficacy and safety, for medications that may be given for much of someone's life, continued assessment of these outcomes is necessary. Furthermore, the CF community must evaluate and address the issues that arise with increased longevity including parenthood, preventive care management and the potential comorbidities of aging.

Interindividual immune variability is driven predominantly by environmental factors, including exposure to chronic infectious agents such as cytomegalovirus (CMV). We investigated the effects of rhesus CMV (RhCMV) on composition and function of the immune system in young macaques. Within months of infection, RhCMV was associated with impressive changes in antigen presenting cells, T cells, and NK cells—and marked expansion of innate-memory CD8(+) T cells. These cells express high levels of NKG2A/C and the IL-2 and IL-15 receptor beta chain, CD122. IL-15 was sufficient to drive differentiation of the cells in vitro and in vivo. Expanded NKG2A/C(+)CD122(+)CD8(+) T cells in RhCMV-infected macaques, but not their NKG2-negative counterparts, were endowed with cytotoxicity against class I–deficient K562 targets and prompt IFN-γ production in response to stimulation with IL-12 and IL-18. Because RhCMV clone 68-1 forms the viral backbone of RhCMV-vectored SIV vaccines, we also investigated immune changes following administration of RhCMV 68-1–vectored SIV vaccines. These vaccines led to impressive expansion of NKG2A/C(+)CD8(+) T cells with capacity to inhibit SIV replication ex vivo. Thus, CMV infection and CMV-vectored vaccination drive expansion of functional innate-like CD8 cells via host IL-15 production, suggesting that innate-memory expansion could be achieved by other vaccine platforms expressing IL-15.

We present measurements of the $E$-mode ($EE$) polarization power spectrum and temperature-$E$-mode ($TE$) cross-power spectrum of the cosmic microwave background using data collected by SPT-3G, the latest instrument installed on the South Pole Telescope. This analysis uses observations of a 1500 deg$^2$ region at 95, 150, and 220 GHz taken over a four month period in 2018. We report binned values of the $EE$ and $TE$ power spectra over the angular multipole range $300 \le \ell < 3000$, using the multifrequency data to construct six semi-independent estimates of each power spectrum and their minimum-variance combination. These measurements improve upon the previous results of SPTpol across the multipole ranges $300 \le \ell \le 1400$ for $EE$ and $300 \le \ell \le 1700$ for $TE$, resulting in constraints on cosmological parameters comparable to those from other current leading ground-based experiments. We find that the SPT-3G dataset is well-fit by a $\Lambda$CDM cosmological model with parameter constraints consistent with those from Planck and SPTpol data. From SPT-3G data alone, we find $H_0 = 68.8 \pm 1.5 \mathrm{km\,s^{-1}\,Mpc^{-1}}$ and $\sigma_8 = 0.789 \pm 0.016$, with a gravitational lensing amplitude consistent with the $\Lambda$CDM prediction ($A_L = 0.98 \pm 0.12$). We combine the SPT-3G and the Planck datasets and obtain joint constraints on the $\Lambda$CDM model. The volume of the 68% confidence region in six-dimensional $\Lambda$CDM parameter space is reduced by a factor of 1.5 compared to Planck-only constraints, with only slight shifts in central values. We note that the results presented here are obtained from data collected during just half of a typical observing season with only part of the focal plane operable, and that the active detector count has since nearly doubled for observations made with SPT-3G after 2018.

SPT-3G is a polarization-sensitive receiver, installed on the South Pole Telescope, that measures the anisotropy of the cosmic microwave background (CMB) from degree to arcminute scales. The receiver consists of ten 150~mm-diameter detector wafers, containing a total of 16,000 transition-edge sensor (TES) bolometers observing at 95, 150, and 220 GHz. During the 2018-2019 austral summer, one of these detector wafers was replaced by a new wafer fabricated with Al-Mn TESs instead of the Ti/Au design originally deployed for SPT-3G. We present the results of in-lab characterization and on-sky performance of this Al-Mn wafer, including electrical and thermal properties, optical efficiency measurements, and noise-equivalent temperature. In addition, we discuss and account for several calibration-related systematic errors that affect measurements made using frequency-domain multiplexing readout electronics., Comment: 9 pages, 5 figures, submitted to the Journal of Low Temperature Physics: LTD18 Special Edition

Hydrocarbon systems with declining or viscous oil production are often stimulated using enhanced oil recovery (EOR) techniques, such as the injection of water, steam, and CO2, in order to increase oil and gas production. As EOR and other methods of enhancing production such as hydraulic fracturing have become more prevalent, environmental concerns about the impact of both new and historical hydrocarbon production on overlying shallow aquifers have increased. Noble gas isotopes are powerful tracers of subsurface fluid provenance and can be used to understand the impact of EOR on hydrocarbon systems and potentially overlying aquifers. In oil systems, produced fluids can consist of a mixture of oil, water and gas. Noble gases are typically measured in the gas phase; however, it is not always possible to collect gases and therefore produced fluids (which are water, oil, and gas mixtures) must be analyzed. We outline a new technique to separate and analyze noble gases in multiphase hydrocarbon-associated fluid samples. An offline double capillary method has been developed to quantitatively isolate noble gases into a transfer vessel, while effectively removing all water, oil, and less volatile hydrocarbons. The gases are then cleaned and analyzed using standard techniques. Air-saturated water reference materials (n = 24) were analyzed and results show a method reproducibility of 2.9% for 4He, 3.8% for 20Ne, 4.5% for 36Ar, 5.3% for 84Kr, and 5.7% for 132Xe. This new technique was used to measure the noble gas isotopic compositions in six produced fluid samples from the Fruitvale Oil Field, Bakersfield, California.

Carbon and other volatiles in the form of gases, fluids or mineral phases are transported from Earth's surface into the mantle at convergent margins, where the oceanic crust subducts beneath the continental crust. The efficiency of this transfer has profound implications for the nature and scale of geochemical heterogeneities in Earth's deep mantle and shallow crustal reservoirs, as well as Earth's oxidation state. However, the proportions of volatiles released from the forearc and backarc are not well constrained compared to fluxes from the volcanic arc front. Here we use helium and carbon isotope data from deeply sourced springs along two cross-arc transects to show that about 91 per cent of carbon released from the slab and mantle beneath the Costa Rican forearc is sequestered within the crust by calcite deposition. Around an additional three per cent is incorporated into the biomass through microbial chemolithoautotrophy, whereby microbes assimilate inorganic carbon into biomass. We estimate that between 1.2 × 108 and 1.3 × 1010 moles of carbon dioxide per year are released from the slab beneath the forearc, and thus up to about 19 per cent less carbon is being transferred into Earth's deep mantle than previously estimated.

In central California, irrigation seepage perturbs groundwater inorganic carbon chemistry and complicates radiocarbon dating., Groundwater is an important source of drinking and irrigation water. Dating groundwater informs its vulnerability to contamination and aids in calibrating flow models. Here, we report measurements of multiple age tracers (14C, 3H, 39Ar, and 85Kr) and parameters relevant to dissolved inorganic carbon (DIC) from 17 wells in California’s San Joaquin Valley (SJV), an agricultural region that is heavily reliant on groundwater. We find evidence for a major mid-20th century shift in groundwater DIC input from mostly closed- to mostly open-system carbonate dissolution, which we suggest is driven by input of anthropogenic carbonate soil amendments. Crucially, enhanced open-system dissolution, in which DIC equilibrates with soil CO2, fundamentally affects the initial 14C activity of recently recharged groundwater. Conventional 14C dating of deeper SJV groundwater, assuming an open system, substantially overestimates residence time and thereby underestimates susceptibility to modern contamination. Because carbonate soil amendments are ubiquitous, other groundwater-reliant agricultural regions may be similarly affected.

Background Participation in research can be beneficial for patients and healthcare providers, but may prove demanding at patient, clinician and organizational levels. Patient representatives are supportive of online research to overcome these challenges. The aim of this pilot study was to develop an online recruitment platform and test its feasibility and acceptability while evaluating the accuracy of participant-reported data. Methods The online research platform was developed in a 1-day ‘hackathon’ with a digital design company. Women who underwent implant-based breast reconstruction in 2011–2016 were invited by letter containing the web address (URL) of the study site and their unique study number. Once online, participants learned about the study, consented, entered data on demographics, treatment received and patient-reported outcome measures (BREAST-Q™), and booked an appointment for a single hospital visit for three-dimensional surface imaging (3D-SI). Real-time process evaluation was performed. The primary endpoint was recruitment rate. Results The recruitment rate was 40 per cent. Of the 100 women, 50 logged on to the platform and 40 completed the process through to 3D-SI. The majority of discontinuations after logging on occurred between consenting and entering demographics (3 women, 6 per cent), and between completing the BREAST-Q and booking an appointment for 3D-SI using the online calendar (3 women, 6 per cent). All women completed the online BREAST-Q™ once started. Participants took a median of 23 minutes to complete the online process. Patient-reported clinical data were accurate in 12 of 13 domains compared with electronic records (95 per cent concordance). Process evaluation demonstrated acceptability. Conclusion The results of this pilot demonstrate the online platform to be acceptable, feasible, and accurate for this population from a single institution. The low-burden design may enable participation from centres with less research support and participants from hard-to-reach groups or dispersed geographical locations, but with online access., Participation in research in beneficial but can be challenging at a participant, clinician and organisation level. A novel online recruitment and data collection platform has been designed to improve accessibility to research and reduce the burden for participants and centres. The pilot study has demonstrated the platform to be feasible, acceptable to patients and accurate. Useful template when resources limited.

Introduction Three-dimensional surface imaging (3D-SI) of the breasts enables the measurement of anthropometric distances and breast volume. These measurements may be used in surgical planning and to facilitate clear communication with patients. The aim of this study was to compare measurements using a portable 3D-SI system, Crisalix, with a more established non-mobile camera, the VECTRA XT. Methods Participants were imaged three times using the Crisalix and the VECTRA XT system. Breast volume, sternal notch to nipple distance, nipple to nipple distance and breast width were measured. Intra-observer agreement was measured using the co-efficient of variation (CV). Agreement between the two methods was represented with Bland Altman agreement plots. Results Intra-method variation was low for both methods (maximum CV 3.3% for Crisalix and 3.2% for VECTRA XT), with only nipple-to-nipple distance being statistically significant, marginally in favour of VECTRA. The mean inter-method differences were small but the limits of agreement (LoA) were wide for all parameters: best for sternal notch to nipple distance, mean difference (MD) -0.03cm and LoA 1.8 to -1.8cm; the widest LoA were for breast volume: MD 31.1cm3 and LoA 286.7 to -244.6cm3. Conclusion This is the first comparison of anthropometric distances and breast volume measured using the two most widely used 3D-SI systems, Crisalix and VECTRA XT. Intra-method variation is low but currently it would not be appropriate to use the two systems interchangeably due to the wide limits of agreement for all four parameters assessed.

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care., CFTR modulator drugs target the underlying cellular defect in cystic fibrosis. They have a range of pulmonary and multisystem effects and are leading to a transformation of care for a majority of people with cystic fibrosis. https://bit.ly/3nfEt8i

Significance We report the discovery of anomalously high 3He/4He in “cold” geothermal fluids of central Panama, far from any active volcanoes. Combined with independent constraints from lava geochemistry, mantle source geochemical anomalies in Central America require a Galápagos plume contribution that is not derived from hotspot track recycling. Instead, these signals likely originate from large-scale transport of Galápagos plume material at sublithospheric depths. Mantle flow modeling and geophysical observations further indicate these geochemical anomalies could result from a Galápagos plume-influenced asthenospheric “mantle wind” that is actively “blowing” through a slab window beneath central Panama. The lateral transport of plume material represents a potentially widespread yet underappreciated mechanism that scatters enriched geochemical signatures in mantle domains far from plumes., It is well established that mantle plumes are the main conduits for upwelling geochemically enriched material from Earth's deep interior. The fashion and extent to which lateral flow processes at shallow depths may disperse enriched mantle material far (>1,000 km) from vertical plume conduits, however, remain poorly constrained. Here, we report He and C isotope data from 65 hydrothermal fluids from the southern Central America Margin (CAM) which reveal strikingly high 3He/4He (up to 8.9RA) in low-temperature (≤50 °C) geothermal springs of central Panama that are not associated with active volcanism. Following radiogenic correction, these data imply a mantle source 3He/4He >10.3RA (and potentially up to 26RA, similar to Galápagos hotspot lavas) markedly greater than the upper mantle range (8 ± 1RA). Lava geochemistry (Pb isotopes, Nb/U, and Ce/Pb) and geophysical constraints show that high 3He/4He values in central Panama are likely derived from the infiltration of a Galápagos plume–like mantle through a slab window that opened ∼8 Mya. Two potential transport mechanisms can explain the connection between the Galápagos plume and the slab window: 1) sublithospheric transport of Galápagos plume material channeled by lithosphere thinning along the Panama Fracture Zone or 2) active upwelling of Galápagos plume material blown by a “mantle wind” toward the CAM. We present a model of global mantle flow that supports the second mechanism, whereby most of the eastward transport of Galápagos plume material occurs in the shallow asthenosphere. These findings underscore the potential for lateral mantle flow to transport mantle geochemical heterogeneities thousands of kilometers away from plume conduits.

The Mexico-UK Sub-Millimetre Camera for AsTronomy (MUSCAT) is a 1.1-mm band receiver consisting of 1,500 single-colour lumped-element kinetic inductance detectors and is scheduled for deployment to the Large Millimeter Telescope (LMT) after the ongoing COVID-19 pandemic. MUSCAT is designed to utilise the full field of view of the LMT's upgraded 50-m primary mirror (approximately 4′). Here we will present the as-measured performance of MUSCAT from the final lab-verification testing prior to shipping to the LMT. We will also explain the overall design of MUSCAT including the novel technologies utilised—such as continuous cooling using sorption coolers and a miniature dilutor, and horn-coupled LEKIDs—for which MUSCAT will provide a first on-sky demonstration.

Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the only available RhCMV clone that permits genetic modifications is based on the 68–1 strain which has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptations. As a result, 68–1 displays reduced viremia in RhCMV-naïve animals and limited shedding compared to non-clonal, low passage isolates. To overcome this limitation, we used sequence information from primary RhCMV isolates to construct a full-length (FL) RhCMV by repairing all mutations affecting open reading frames (ORFs) in the 68–1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naïve RM with the reconstituted virus resulted in significant viremia in the blood similar to primary isolates of RhCMV and furthermore led to high viral genome copy numbers in many tissues at day 14 post infection. In contrast, viral dissemination was greatly reduced upon deletion of genes also lacking in 68–1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68–1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques., Author summary Human cytomegalovirus (HCMV) infections are generally asymptomatic in healthy immunocompetent individuals, but HCMV can cause serious disease after congenital infection and in individuals with immunocompromised immune systems. Since HCMV is highly species specific and cannot productively infect immunocompetent laboratory animals, experimental infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a closely related animal model for HCMV. By employing the unique ability of CMV to elicit robust and lasting cellular immunity, this model has also been instrumental in developing novel CMV-based vaccines against chronic and recurring infections with pathogens such as the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb). However, most of this work was conducted with derivatives of the 68–1 strain of RhCMV which has acquired multiple genomic alterations in tissue culture. To model pathogenesis and immunology of clinical HCMV isolates we generated a full-length (FL) RhCMV clone representative of low passage isolates. Infection of RhCMV-naïve RM with FL-RhCMV demonstrated viremia and tissue dissemination that was comparable to that of non-clonal low passage isolates. We further demonstrate that FL-RhCMV is strongly attenuated upon deletion of gene regions absent in 68–1 thus demonstrating the usefulness of FL-RhCMV to study RhCMV pathogenesis.

Arrays of lumped-element kinetic inductance detectors (LEKIDs) optically coupled through an antenna-coupled transmission line are a promising candidate for future cosmic microwave background (CMB) experiments. However, the dielectric materials used for the microstrip architecture are known to degrade the performance of superconducting resonators. In this paper, we investigate the feasibility of microstrip coupling to a LEKID, focusing on a systematic study of the effect of depositing amorphous silicon-nitride on a LEKID. The discrete and spatially-separated inductive and capacitive regions of the LEKID allow us to vary the degree of dielectric coverage and determine the limitations of the microstrip coupling architecture. We show that by careful removal of dielectric from regions of high electric field in the capacitor, there is minimal degradation in dielectric loss tangent of a partially covered lumped-element resonator. We present the effects on the resonant frequency and noise power spectral density and, using the dark responsivity, provide an estimate for the resulting detector sensitivity., Comment: Presented at the 18th International Workshop on Low Temperature Detectors. Published in the Journal of Low Temperature Physics

PURPOSE To assess the effectiveness of current antiseptic agents on multidrug-resistant (MDR) isolates in an in vitro setting. SETTING Department of Microbiology, The National Maternity Hospital, Dublin, Ireland. DESIGN Organisms were selected based on current review of endophthalmitis literature: methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), Pseudomonas aeruginosa, carbapenem-resistant and extended-spectrum β-lactamase Klebsiella pneumoniae, and vancomycin-resistant (VRE) Enterococcus faecalis. METHODS Samples were exposed to povidone-iodine (PVI) 5% and chlorhexidine (CHX) 0.05% for 0.5 minutes, 1 minute, 3 minutes, and 5 minutes. After inactivation, organisms were incubated under standard conditions and growth assessed after 16 hours. RESULTS MRSA and MRSE responded to 3-minute PVI exposure. CHX eradicated MRSA growth after 5 minutes but failed to completely suppress MRSE. Pseudomonas and Klebsiella required 3-minute CHX exposure and 5-minute PVI exposure for complete clearance. Eradication of enterococci (VRE positive and negative) was not achieved at 10 minutes of CHX or PVI exposure. Comparison of PVI vs CHX showed a benefit for PVI in MRSA (P < .01) and MRSE (P < .001) eradication at 3 minutes. CONCLUSIONS Current recommendations of 3 minutes of antisepsis prior to intraocular surgery are not sufficient for complete eradication of MDR organisms from the ocular surface. A bespoke approach is suggested to patients at risk for carriage of MDR organisms to minimize the risk of endophthalmitis.

Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (RhCMV/SIV) vaccines are associated with complete clearance of pathogenic SIV challenge virus, non-canonical major histocompatibility complex restriction, and absent antibody responses in recipients previously infected with wild-type RhCMV. This report presents the first investigation of RhCMV/SIV vaccines in RhCMV-seronegative macaques lacking anti-vector immunity. Fifty percent of rhesus macaques (RM) vaccinated with a combined RhCMV-Gag, -Env, and -Retanef (RTN) vaccine controlled pathogenic SIV challenge despite high peak viremia. However, kinetics of viral load control by vaccinated RM were considerably delayed compared to previous reports. Impact of a TLR5 agonist (flagellin; FliC) on vaccine efficacy and immunogenicity was also examined. An altered vaccine regimen containing an SIV Gag-FliC fusion antigen instead of Gag was significantly less immunogenic and resulted in reduced protection. Notably, RhCMV-Gag and RhCMV-Env vaccines elicited anti-Gag and anti-Env antibodies in RhCMV-seronegative RM, an unexpected contrast to vaccination of RhCMV-seropositive RM. These findings confirm that RhCMV-vectored SIV vaccines significantly protect against SIV pathogenesis. However, pre-existing vector immunity and a pro-inflammatory vaccine adjuvant may influence RhCMV/SIV vaccine immunogenicity and efficacy. Future investigation of the impact of pre-existing anti-vector immune responses on protective immunity conferred by this vaccine platform is warranted.

Ivacaftor was the first therapy licensed to address the underlying defect in cystic fibrosis (CF). The improvements in lung function, nutritional status and pulmonary exacerbations in patients carrying aWe conducted a 5-year single-centre retrospective study of people with CF carrying the35 people were included. After commencing ivacaftor, FEVThe addition of ivacaftor provides acute benefits for people with the

Significance Volatile elements play a critical role in the evolution of Earth. Nevertheless, the mechanism(s) by which Earth acquired, and was able to preserve its volatile budget throughout its violent accretionary history, remains uncertain. In this study, we analyzed noble gas isotopes in volcanic gases from the Yellowstone mantle plume, thought to sample the deep primordial mantle, to determine the origin of volatiles on Earth. We find that Kr and Xe isotopes within the deep mantle have a similar chondritic origin to those found previously in the upper mantle. This suggests that the Earth has retained chondritic volatiles throughout the accretion and, therefore, terrestrial volatiles cannot not solely be the result of late additions following the Moon-forming impact., Identifying the origin of noble gases in Earth’s mantle can provide crucial constraints on the source and timing of volatile (C, N, H2O, noble gases, etc.) delivery to Earth. It remains unclear whether the early Earth was able to directly capture and retain volatiles throughout accretion or whether it accreted anhydrously and subsequently acquired volatiles through later additions of chondritic material. Here, we report high-precision noble gas isotopic data from volcanic gases emanating from, in and around, the Yellowstone caldera (Wyoming, United States). We show that the He and Ne isotopic and elemental signatures of the Yellowstone gas requires an input from an undegassed mantle plume. Coupled with the distinct ratio of 129Xe to primordial Xe isotopes in Yellowstone compared with mid-ocean ridge basalt (MORB) samples, this confirms that the deep plume and shallow MORB mantles have remained distinct from one another for the majority of Earth’s history. Krypton and xenon isotopes in the Yellowstone mantle plume are found to be chondritic in origin, similar to the MORB source mantle. This is in contrast with the origin of neon in the mantle, which exhibits an isotopic dichotomy between solar plume and chondritic MORB mantle sources. The co-occurrence of solar and chondritic noble gases in the deep mantle is thought to reflect the heterogeneous nature of Earth’s volatile accretion during the lifetime of the protosolar nebula. It notably implies that the Earth was able to retain its chondritic volatiles since its earliest stages of accretion, and not only through late additions.