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This thesis investigates Canadian prairie plants as sources of natural product compounds capable of inhibiting human cell division. Natural products present an opportunity to identify novel anti-mitotic compounds to address the lack of known inhibitors for many mitotic regulatory proteins. By biology-guided fractionation, we purified the natural products anemonin from Pulsatilla nuttalliana and (+)-6-tuliposide A from Erythronium grandiflorum, and this is the first report of their anti-mitotic activities. We then conducted a comparative study between pulchelloid A (from Gaillardia aristata), anemonin and (+)-6-tuliposide A, and identified unique mitotic arrest profiles, suggesting distinct protein targets and mechanisms of action consistent with the widespread relationship between structure and function in biology. The discovery of natural product inhibitors from Canadian prairie plant species holds tremendous potential for advancing our understanding of mitotic regulation and contributes to the development of targeted treatments for precision medicine.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

Venus, lacking an intrinsic global dipole magnetic field, serves as a textbook example of an induced magnetosphere, formed by interplanetary magnetic fields (IMF) enveloping the planet. Yet, various aspects of its magnetospheric dynamics and planetary ion outflows are complex and not well understood. Here we analyze plasma and magnetic field data acquired during the fourth Venus flyby of the Parker Solar Probe (PSP) mission and show evidence for closed topology in the nightside and downstream portion of the Venus magnetosphere (i.e., the magnetotail). The formation of the closed topology involves magnetic reconnection-a process rarely observed at non-magnetized planets. In addition, our study provides an evidence linking the cold Venusian ion flow in the magnetotail directly to magnetic connectivity to the ionosphere, akin to observations at Mars. These findings not only help the understanding of the complex ion flow patterns at Venus but also suggest that magnetic topology is one piece of key information for resolving ion escape mechanisms and thus the atmospheric evolution across various planetary environments and exoplanets. Magnetic reconnection dynamics in Venus' magnetosphere are not well-known due to limited observations. Here, the authors show direct evidence for closed magnetic topology in Venus' magnetotail and a link between the cold ion flow in the magnetotail and its direct magnetic connectivity to the ionosphere.

The Simons Observatory (SO) is a cosmic microwave background instrumentation suite in the Atacama Desert of Chile. More than 65,000 polarization-sensitive transition-edge sensor (TES) bolometers will be fielded in the frequency range spanning 27 to 280 GHz, with three separate dichroic designs. The mid-frequency 90/150 GHz and ultra-high-frequency 220/280 GHz detector arrays, fabricated at NIST, account for 39 of 49 total detector modules and implement the feedhorn-fed orthomode transducer (OMT)-coupled TES bolometer architecture. A robust production-level fabrication framework for these detector arrays and the monolithic DC/RF routing wafers has been developed, which includes single device prototyping, process monitoring techniques, in-process metrology, and cryogenic measurements of critical film properties. Application of this framework has resulted in timely delivery of nearly 100 total superconducting focal plane components to SO with 88% of detector wafers meeting nominal criteria for integration into a detector module: a channel yield > 95% and Tc in the targeted range., Comment: 10 pages, 6 figures. Proceedings of the 20th International Conference on Low Temperature Detectors (LTD20). Submitted to JLTP

Impacts are critical to producing the aqueous environments necessary to stimulate prebiotic chemistry on Titan's surface. Furthermore, organic hazes resting on the surface are a likely feedstock of biomolecules. In this work, we conduct impact experiments on laboratory-produced organic haze particles and haze/sand mixtures and analyze these samples for life's building blocks. Samples of unshocked haze and sand particles are also analyzed to determine the change in biomolecule concentrations and distributions from shocking. Across all samples, we detect seven nucleobases, nine proteinogenic amino acids, and five other biomolecules (e.g., urea) using a blank subtraction procedure to eliminate signals due to contamination. We find that shock pressures of 13 GPa variably degrade nucleobases, amino acids, and a few other organics in haze particles and haze/sand mixtures; however, certain individual biomolecules become enriched or are even produced from these events. Xanthine, threonine, and aspartic acid are enriched or produced in impact experiments containing sand, suggesting these minerals may catalyze the production of these biomolecules. On the other hand, thymine and isoleucine/norleucine are enriched or produced in haze samples containing no sand, suggesting catalytic grains are not necessary for all impact shock syntheses. Uracil, glycine, proline, cysteine, and tyrosine are the most unstable to impact-related processing. These experiments suggest that impacts alter biomolecule distributions on Titan's surface, and that organic hazes co-occurring with fine-grained material on the surface may provide an initial source for further prebiotic chemistry on Titan., Comment: Accepted to PSJ. 13 pages, 3 tables, 7 figures

ObjectivesWhat sonographic variables are most predictive for acute cholecystitis? What variables differentiate acute and chronic cholecystitis?MethodsThe surgical pathology database was reviewed to identify adult patients who underwent cholecystectomy for cholecystitis and had a preceding ultrasound of the right upper quadrant within 7 days. A total of 236 patients were included in the study. A comprehensive imaging review was performed to assess for gallstones, gallbladder wall thickening, gallbladder distension, pericholecystic fluid, gallstone mobility, the sonographic Murphy's sign, mural hyperemia, and the common hepatic artery peak systolic velocity.ResultsOf 236 patients with a cholecystectomy, 119 had acute cholecystitis and 117 had chronic cholecystitis on surgical pathology. Statistical models were created for prediction. The simple model consists of three sonographic variables and has a sensitivity of 60% and specificity of 83% in predicting acute versus chronic cholecystitis. The most predictive variables for acute cholecystitis were elevated common hepatic artery peak systolic velocity, gallbladder distension, and gallbladder mural abnormalities. If a patient had all three of these findings on their preoperative ultrasound, the patient had a 96% chance of having acute cholecystitis. Two of these variables gave a 73-93% chance of having acute cholecystitis. One of the three variables gave a 40-76% chance of having acute cholecystitis. If the patient had 0 of 3 of the predictor variables, there was a 29% chance of having acute cholecystitis.ConclusionsGallbladder distension, gallbladder mural abnormalities, and elevated common hepatic artery peak systolic velocity are the most important sonographic variables in predicting acute versus chronic cholecystitis.

Retained lead fragments from nonfatal firearm injuries pose a risk of lead poisoning. While chelation is well-established as a lead poisoning treatment, it remains unclear whether chelation mobilizes lead from embedded lead fragments. Here, we tested whether 1) DMSA/succimer or CaNa2EDTA increases mobilization of lead from fragments in vitro, and 2) succimer is efficacious in chelating fragment lead in vivo, using stable lead isotope tracer methods in a rodent model of embedded fragments. DMSA was >10-times more effective than CaNa2EDTA in mobilizing fragment lead in vitro. In the rodent model, succimer chelation on day 1 produced the greatest blood lead reductions, and fragment lead was not mobilized into blood. However, with continued chelation and over 3-weeks post-chelation, blood lead levels rebounded with mobilization of lead from the fragments. These findings suggest prolonged chelation will increase fragment lead mobilization post-chelation, supporting the need for long-term surveillance in patients with retained fragments.

BackgroundInternationally, strategies focusing on reducing alcohol-related harms in homeless populations with severe alcohol use disorder (AUD) continue to gain acceptance, especially when conventional modalities focused on alcohol abstinence have been unsuccessful. One such strategy is the managed alcohol program (MAP), an alcohol harm reduction program managing consumption by providing eligible individuals with regular doses of alcohol as a part of a structured program, and often providing resources such as housing and other social services. Evidence to the role of MAPs for individuals with AUD, including how MAPs are developed and implemented, is growing. Yet there has been limited collective review of literature findings.MethodsWe conducted a scoping review to answer, "What is being evaluated in studies of MAPs? What factors are associated with a successful MAP, from the perspective of client outcomes? What are the factors perceived as making them a good fit for clients and for communities?" We first conducted a systematic search in PubMed, Embase, PsycINFO, CINAHL, Sociological Abstracts, Social Services Abstracts, and Google Scholar. Next, we searched the gray literature (through focused Google and Ecosia searches) and references of included articles to identify additional studies. We also contacted experts to ensure relevant studies were not missed. All articles were independently screened and extracted.ResultsWe included 32 studies with four categories of findings related to: (1) client outcomes resulting from MAP participation, (2) client experience within a MAP; (3) feasibility and fit considerations in MAP development within a community; and (4) recommendations for implementation and evaluation. There were 38 established MAPs found, of which 9 were featured in the literature. The majority were located in Canada; additional research works out of Australia, Poland, the USA, and the UK evaluate potential feasibility and fit of a MAP.ConclusionsThe growing li

This paper describes the evaluation of a longitudinal peer-support program developed to address loneliness and isolation among low-income, urban community-dwelling older adults in San Francisco. Our objective was to determine barriers, challenges, and successful strategies in implementation of the program. In-depth qualitative interviews with clients (n = 15) and peers (n = 6) were conducted and analyzed thematically by program component. We identified barriers and challenges to engagement and outlined strategies used to identify clients, match them with peers, and provide support to both peers and clients. We found that peers played a flexible, non-clinical role and were perceived as friends. Connections to community resources helped when clients needed additional support. We also documented creative strategies used to maintain inter-personal connections during the COVID-19 pandemic. This study fills a gap in understanding how a peer-support program can be designed to address loneliness and social isolation, particularly in low-income, urban settings.

Background: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS. Methods: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. Results: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those <5.0 mg/dL. Median TB levels between ≥5.0 and <10.0 mg/dL and >10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to <5.0 mg/dL. Median TB <5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p<0.001). Conclusions: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.

Changing climates are altering the structural and functional components of forest ecosystems at an unprecedented rate. Simultaneously, we are seeing a diversification of public expectations on the broader sustainable use of forest resources beyond timber production. As a result, the science and art of silviculture needs to adapt to these changing realities. In this piece, we argue that silviculturists are gradually shifting from the application of empirically derived silvicultural scenarios to new sets of approaches, methods and practices, a process that calls for broadening our conception of silviculture as a scientific discipline. We propose a holistic view of silviculture revolving around three key themes: observe, anticipate and adapt. In observe, we present how recent advances in remote sensing now enable silviculturists to observe forest structural, compositional and functional attributes in near-real-time, which in turn facilitates the deployment of efficient, targeted silvicultural measures in practice that are adapted to rapidly changing constraints. In anticipate, we highlight the importance of developing state-of-the-art models designed to take into account the effects of changing environmental conditions on forest growth and dynamics. In adapt, we discuss the need to provide spatially explicit guidance for the implementation of adaptive silvicultural actions that are efficient, cost-effective and socially acceptable. We conclude by presenting key steps towards the development of new tools and practical knowledge that will ensure meeting societal demands in rapidly changing environmental conditions. We classify these actions into three main categories: reexamining existing silvicultural trials to identify key stand attributes associated with the resistance and resilience of forests to multiple stressors, developing technological workflows and infrastructures to allow for continuous forest inventory updating frameworks, and implementing bold, innovative si

We present cosmological constraints from a gravitational lensing mass map covering 9400 sq. deg. reconstructed from CMB measurements made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with BAO measurements (from SDSS and 6dF), we obtain the amplitude of matter fluctuations $\sigma_8 = 0.819 \pm 0.015$ at 1.8% precision, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.840\pm0.028$ and the Hubble constant $H_0= (68.3 \pm 1.1)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$ at 1.6% precision. A joint constraint with CMB lensing measured by the Planck satellite yields even more precise values: $\sigma_8 = 0.812 \pm 0.013$, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.831\pm0.023$ and $H_0= (68.1 \pm 1.0)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$. These measurements agree well with $\Lambda$CDM-model extrapolations from the CMB anisotropies measured by Planck. To compare these constraints to those from the KiDS, DES, and HSC galaxy surveys, we revisit those data sets with a uniform set of assumptions, and find $S_8$ from all three surveys are lower than that from ACT+Planck lensing by varying levels ranging from 1.7-2.1$\sigma$. These results motivate further measurements and comparison, not just between the CMB anisotropies and galaxy lensing, but also between CMB lensing probing $z\sim 0.5-5$ on mostly-linear scales and galaxy lensing at $z\sim 0.5$ on smaller scales. We combine our CMB lensing measurements with CMB anisotropies to constrain extensions of $\Lambda$CDM, limiting the sum of the neutrino masses to $\sum m_{\nu} < 0.12$ eV (95% c.l.), for example. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the $\Lambda$CDM model, while paving a promising path for neutrino physics with gravitational lensing from upcoming ground-based CMB surveys., Comment: 30 pages, 16 figures, prepared for submission to ApJ. Cosmological likelihood data is here: https://lambda.gsfc.nasa.gov/product/act/actadv_prod_table.html ; likelihood software is here: https://github.com/ACTCollaboration/act_dr6_lenslike . Also see companion papers Qu et al and MacCrann et al. Mass maps will be released when papers are published

Objective: We aimed to determine the longitudinal distribution of hand function skills in individuals with classic Rett syndrome (RTT), an X‐linked dominant neurodevelopmental disorder, and correlate with MECP2 variants. Method: We conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus of this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups. Results: Following the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C‐terminal truncations) compared with groups composed of individuals with more severe variants. Conclusions: These temporal variations in hand use represent specific considerations that could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

In this review, we synthesize evidence to highlight cognitive appraisal as an important developmental antecedent of individual differences in emotion differentiation and adept emotion regulation. Emotion differentiation is the degree to which emotions are experienced in a nuanced or "granular" way-as specific and separable phenomena. More extensive differentiation is related to positive wellbeing and has emerged as a correlate of emotion regulation skill among adults. We argue that the cognitive appraisal processes that underlie these facets of emotional development are instantiated early in the first year of life and tuned by environmental input and experience. Powerful socializing input in the form of caregivers' contingent and selective responding to infants' emotional signals carves and calibrates the infant's appraisal thresholds for what in their world ought to be noticed, deemed as important or personally meaningful, and responded to (whether and how). These appraisal thresholds are thus unique to the individual child despite the ubiquity of the appraisal process in emotional responding. This appraisal infrastructure, while plastic and continually informed by experience across the lifespan, likely tunes subsequent emotion differentiation, with implications for children's emotion regulatory choices and skills. We end with recommendations for future research in this area, including the urgent need for developmental emotion science to investigate the diverse sociocultural contexts in which children's cognitive appraisals, differentiation of emotions, and regulatory responses are being built across childhood.

Introduction This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of RO7297089, an anti-BCMA/CD16a bispecific antibody. Methods RO7297089 was administered weekly by intravenous infusion to patients with relapsed/refractory multiple myeloma. The starting dose was 60 mg in this dose-escalation study utilizing a modified continual reassessment method with overdose control model. Results Overall, 27 patients were treated at doses between 60 and 1850 mg. The maximally administered dose was 1850 mg due to excipients in the formulation that did not allow for higher doses to be used. The maximum tolerated dose was not reached. The most common adverse events irrespective of grade and relationship to the drug were anemia, infusion-related reaction, and thrombocytopenia. Most common treatment-related grade ≥ 3 toxicities were ALT/AST increase and reduced lymphocyte count. Pharmacokinetic studies suggested non-linear pharmacokinetics and target-mediated drug disposition, with a trend of approaching linear pharmacokinetics at doses of 1080 mg and higher. Partial response was observed in two patients (7%), minimal response in two patients (7%), and stable disease in 14 patients (52%). Conclusions RO7297089 was well tolerated at doses up to 1850 mg, and the efficacy data supported activity of RO7297089 in multiple myeloma. Combination with other agents may further enhance its potential as an innate immune cell engager in multiple myeloma., Introduction: This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of RO7297089, an anti-BCMA/CD16a bispecific antibody. Methods: RO7297089 was administered weekly by intravenous infusion to patients with relapsed/refractory multiple myeloma. The starting dose was 60 mg in this dose-escalation study utilizing a modified continual reassessment method with overdose control model. Results: Overall, 27 patients were treated at doses between 60 and 1850 mg. The maximally administered dose was 1850 mg due to excipients in the formulation that did not allow for higher doses to be used. The maximum tolerated dose was not reached. The most common adverse events irrespective of grade and relationship to the drug were anemia, infusion-related reaction, and thrombocytopenia. Most common treatment-related grade ≥ 3 toxicities were ALT/AST increase and reduced lymphocyte count. Pharmacokinetic studies suggested non-linear pharmacokinetics and target-mediated drug disposition, with a trend of approaching linear pharmacokinetics at doses of 1080 mg and higher. Partial response was observed in two patients (7%), minimal response in two patients (7%), and stable disease in 14 patients (52%). Conclusions: RO7297089 was well tolerated at doses up to 1850 mg, and the efficacy data supported activity of RO7297089 in multiple myeloma. Combination with other agents may further enhance its potential as an innate immune cell engager in multiple myeloma. Trial Registration: ClinicalTrials.gov: NCT04434469; Registered June 16, 2020; https://www.clinicaltrials.gov/ct2/show/NCT04434469.

Observations of the millimeter sky contain valuable information on a number of signals, including the blackbody cosmic microwave background (CMB), Galactic emissions, and the Compton-$y$ distortion due to the thermal Sunyaev-Zel'dovich (tSZ) effect. Extracting new insight into cosmological and astrophysical questions often requires combining multi-wavelength observations to spectrally isolate one component. In this work, we present a new arcminute-resolution Compton-$y$ map, which traces out the line-of-sight-integrated electron pressure, as well as maps of the CMB in intensity and E-mode polarization, across a third of the sky (around 13,000 sq.~deg.). We produce these through a joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release 4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We present detailed verification of an internal linear combination pipeline implemented in a needlet frame that allows us to efficiently suppress Galactic contamination and account for spatial variations in the ACT instrument noise. These maps provide a significant advance, in noise levels and resolution, over the existing \textit{Planck} component-separated maps and will enable a host of science goals including studies of cluster and galaxy astrophysics, inferences of the cosmic velocity field, primordial non-Gaussianity searches, and gravitational lensing reconstruction of the CMB., Comment: The Compton-y map and associated products will be made publicly available upon publication of the paper. The CMB T and E mode maps will be made available when the DR6 maps are made public

We investigate the impact and mitigation of extragalactic foregrounds for the CMB lensing power spectrum analysis of Atacama Cosmology Telescope (ACT) data release 6 (DR6) data. Two independent microwave sky simulations are used to test a range of mitigation strategies. We demonstrate that finding and then subtracting point sources, finding and then subtracting models of clusters, and using a profile bias-hardened lensing estimator, together reduce the fractional biases to well below statistical uncertainties, with the inferred lensing amplitude, $A_{\mathrm{lens}}$, biased by less than $0.2\sigma$. We also show that another method where a model for the cosmic infrared background (CIB) contribution is deprojected and high frequency data from Planck is included has similar performance. Other frequency-cleaned options do not perform as well, incurring either a large noise cost, or resulting in biased recovery of the lensing spectrum. In addition to these simulation-based tests, we also present null tests performed on the ACT DR6 data which test for sensitivity of our lensing spectrum estimation to differences in foreground levels between the two ACT frequencies used, while nulling the CMB lensing signal. These tests pass whether the nulling is performed at the map or bandpower level. The CIB-deprojected measurement performed on the DR6 data is consistent with our baseline measurement, implying contamination from the CIB is unlikely to significantly bias the DR6 lensing spectrum. This collection of tests gives confidence that the ACT DR6 lensing measurements and cosmological constraints presented in companion papers to this work are robust to extragalactic foregrounds., Comment: Companion paper to Qu et al and Madhavacheril et al

We present new measurements of cosmic microwave background (CMB) lensing over $9400$ sq. deg. of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at $2.3\%$ precision ($43\sigma$ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. The baseline spectrum is well fit by a lensing amplitude of $A_{\mathrm{lens}}=1.013\pm0.023$ relative to the Planck 2018 CMB power spectra best-fit $\Lambda$CDM model and $A_{\mathrm{lens}}=1.005\pm0.023$ relative to the $\text{ACT DR4} + \text{WMAP}$ best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination $S^{\mathrm{CMBL}}_8 \equiv \sigma_8 \left({\Omega_m}/{0.3}\right)^{0.25}$ of $S^{\mathrm{CMBL}}_8= 0.818\pm0.022$ from ACT DR6 CMB lensing alone and $S^{\mathrm{CMBL}}_8= 0.813\pm0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with $\Lambda$CDM model constraints from Planck or $\text{ACT DR4} + \text{WMAP}$ CMB power spectrum measurements. Our lensing measurements from redshifts $z\sim0.5$--$5$ are thus fully consistent with $\Lambda$CDM structure growth predictions based on CMB anisotropies probing primarily $z\sim1100$. We find no evidence for a suppression of the amplitude of cosmic structure at low redshifts, Comment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see companion papers Madhavacheril et al and MacCrann et al

We conduct a systematic search for transients in three years of data (2017-2019) from the Atacama Cosmology Telescope (ACT). ACT covers 40 percent of the sky at three bands spanning from 77 GHz to 277 GHz. Analysis of 3-day mean-subtracted sky maps, which were match-filtered for point sources, yielded 29 transients detections. Eight of these transients are due to known asteroids, and three others were previously published. Four of these events occur in areas of with poor noise models and thus we cannot be confident they are real transients. We are left with 14 new transient events occurring at 11 unique locations. All of these events are associated with either rotationally variable stars or cool stars. Ten events have flat or falling spectra indicating radiation from synchrotron emission. One event has a rising spectrum indicating a different engine for the flare.

Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.

In the Southern Ocean, it is well-known that iron (Fe) limits phytoplankton growth. Yet, other trace metals can also affect phytoplankton physiology. This study investigated feedbacks between phytoplankton growth and dissolved Fe, manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), and cadmium (Cd) concentrations in Southern Ocean shipboard incubations. Three experiments were conducted in September–October 2016 near the West Antarctic Peninsula: Incubations 1 and 3 offshore in the Antarctic Circumpolar Current, and Incubation 2 inshore in Bransfield Strait. Additions of Fe and/or vitamin B12 to inshore and offshore waters were employed and allowed assessment of metal (M) uptake relative to soluble reactive phosphorus (P) across a wide range of initial conditions. Offshore, treatments of >1 nmol L−1 added Fe were Fe-replete, whereas inshore waters were already Fe-replete. Results suggest Mn was a secondary limiting nutrient inshore and offshore. No Fe-vitamin B12 colimitation was observed. Overall, M:P uptake in the incubations was closely related to initial dissolved M:P for Fe, Mn, Co, Ni, and Cd, and for Cu inshore. Final concentrations of Fe and Zn were similar across light treatments of the experiments despite very different phytoplankton responses, and we observed evidence for Co/Cd/Zn substitution and for recycling of biogenic metals as inventories plateaued. In dark bottles, the absence of Mn oxidation may have allowed more efficient recycling of Fe and other trace metals. Our results provide insight into factors governing trace metal uptake, with implications for phytoplankton community composition locally and preformed micronutrient bioavailability in Southern Ocean water masses.

The Simons Observatory (SO) is a cosmic microwave background instrumentation suite being deployed in the Atacama Desert in northern Chile. The telescopes within SO use three types of dichroic transition-edge sensor (TES) detector arrays, with the 90 and 150 GHz Mid-Frequency (MF) arrays containing 65% of the approximately 68,000 detectors in the first phase of SO. All of the 26 required MF detector arrays have now been fabricated, packaged into detector modules, and tested in laboratory cryostats. Across all modules, we find an average operable detector yield of 84% and median saturation powers of (2.8, 8.0) pW with interquartile ranges of (1, 2) pW at (90, 150) GHz, respectively, falling within their targeted ranges. We measure TES normal resistances and superconducting transition temperatures on each detector wafer to be uniform within 3%, with overall central values of 7.5 mohm and 165 mK, respectively. Results on time constants, optical efficiency, and noise performance are also presented and are consistent with achieving instrument sensitivity forecasts., Comment: 8 pages, 3 figures. Proceedings of the 20th International Conference on Low Temperature Detectors (LTD20). Accepted to JLTP

While machine learning (ML) includes a valuable array of tools for analyzing biomedical data, significant time and expertise is required to assemble effective, rigorous, and unbiased pipelines. Automated ML (AutoML) tools seek to facilitate ML application by automating a subset of analysis pipeline elements. In this study we develop and validate a Simple, Transparent, End-to-end Automated Machine Learning Pipeline (STREAMLINE) and apply it to investigate the added utility of photography-based phenotypes for predicting obstructive sleep apnea (OSA); a common and underdiagnosed condition associated with a variety of health, economic, and safety consequences. STREAMLINE is designed to tackle biomedical binary classification tasks while adhering to best practices and accommodating complexity, scalability, reproducibility, customization, and model interpretation. Benchmarking analyses validated the efficacy of STREAMLINE across data simulations with increasingly complex patterns of association. Then we applied STREAMLINE to evaluate the utility of demographics (DEM), self-reported comorbidities (DX), symptoms (SYM), and photography-based craniofacial (CF) and intraoral (IO) anatomy measures in predicting any OSA or moderate/severe OSA using 3,111 participants from Sleep Apnea Global Interdisciplinary Consortium (SAGIC). OSA analyses identified a significant increase in ROC-AUC when adding CF to DEM+DX+SYM to predict moderate/severe OSA. A consistent but non-significant increase in PRC-AUC was observed with the addition of each subsequent feature set to predict any OSA, with CF and IO yielding minimal improvements. Application of STREAMLINE to OSA data suggests that CF features provide additional value in predicting moderate/severe OSA, but neither CF nor IO features meaningfully improved the prediction of any OSA beyond established demographics, comorbidity and symptom characteristics., Comment: 23 pages, 7 figures, 1 table, 1 supplemental information document (77 pages), and 7 ancillary files

ObjectiveThe goal of the present work is to provide an overview of the differential diagnosis of Wilson disease.BackgroundWilson disease is a rare condition due to copper accumulation primarily in the liver and brain. Although there is no definitive cure, current anti-copper treatments are associated with better outcomes if initiated early and if the diagnosis is made promptly. However, diagnostic delays are frequent and often Wilson disease represents a diagnostic challenge. The diagnosis ultimately relies on a combination of clinical, laboratory and genetic findings, and it is crucial that clinicians list Wilson disease in their differential diagnosis, especially in patients presenting with a hepatocellular pattern of liver injury. Some biochemical and liver histological features of Wilson disease overlap with those of more common conditions including nonalcoholic fatty liver disease, alcohol-associated liver disease, and autoimmune hepatitis. In particular, hepatic steatosis, hepatocyte glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies are often identified in Wilson disease as well as more common liver diseases. In addition, the natural history of liver damage in Wilson disease and the risk of developing liver cancer are largely understudied.MethodsWe conducted an enlarged review of published papers on Wilson disease focusing on its diagnosis and distinctive clinical and liver pathology features in relation to common non-cholestatic liver diseases with the final goal in aiding clinicians in the diagnostic process of this rare but treatable condition.ConclusionsAside from markedly altered copper metabolism, Wilson disease has essentially no pathognomonic features that can distinguish it from more common liver diseases. Clinicians should be aware of this challenge and consider Wilson disease in patients presenting with a hepatocellular pattern of liver injury.

Human papillomavirus (HPV) vaccination rates in the U.S. are relatively low. Provider recommendation rates for HPV vaccination often vary by patient age and relationship status. Obstetrician/gynecologists (OB/GYNs) represent a key provider group that can recommend the HPV vaccine. This study examined differences in OB/ GYN recommendation of HPV vaccination for inpatient postpartum patients by age, parity, and marital status. Data were collected from OB/GYNs nationally via a cross-sectional survey. Participants were randomized to two vignette groups (23-year-old patient or 33-year-old patient). Within each group, participants received 4 vignettes that were identical except for patient marital status (married/not in a committed relationship) and number of children (first/third child), and were asked to indicate HPV vaccination recommendation likelihood on a scale of 0 (definitely would not) to 100 (definitely would). A 2 × 2 × 2 general linear model with repeated measures was used to examine main and interaction effects of patient age, relationship status, and parity. 207 OB/GYNs were included in the final analyses. Recommendation was high for 23-year-old patients (range: 64.5–84.6 out of 100). When marital status and parity were held constant, recommendation likelihood was higher for the younger vs. older patient and was also higher for patients not in a committed relationship, compared to married patients (all p-values < 0.001). Differences in recommendation exist when considering age and relationship status, which provides insight into OB/GYN clinical decision-making. Findings highlight the need to address barriers to HPV vaccination recommendation, including awareness of risk factors to consider when recommending the vaccine.

The Simons Observatory (SO) is a suite of instruments sensitive to temperature and polarization of the cosmic microwave background (CMB) to be located at Cerro Toco in the Atacama Desert in Chile. Five telescopes, one large aperture telescope and four small aperture telescopes, will host roughly 70,000 highly multiplexed transition edge sensor (TES) detectors operated at 100 mK. Each SO focal plane module (UFM) couples 1,764 TESes to microwave resonators in a microwave multiplexing (uMux) readout circuit. Before detector integration, the 100 mK uMux components are packaged into multiplexing modules (UMMs), which are independently validated to ensure they meet SO performance specifications. Here we present the assembly developments of these UMM readout packages for mid frequency (90/150 GHz) and ultra high frequency (220/280 GHz) UFMs.

This is a solicited whitepaper for the Snowmass 2021 community planning exercise. The paper focuses on measurements and science with the Cosmic Microwave Background (CMB). The CMB is foundational to our understanding of modern physics and continues to be a powerful tool driving our understanding of cosmology and particle physics. In this paper, we outline the broad and unique impact of CMB science for the High Energy Cosmic Frontier in the upcoming decade. We also describe the progression of ground-based CMB experiments, which shows that the community is prepared to develop the key capabilities and facilities needed to achieve these transformative CMB measurements., Comment: contribution to Snowmass 2021

With increasing pressure for climate action, commitments to setting scientifically supported emissions targets have become more common among firms. The target-setting methods currently endorsed by the Science Based Targets Initiative (SBTi) use emission pathways that are aligned with 1.5°C and well-below 2°C long-term temperature goals to inform near-term corporate targets. However, most of these scenarios lead to a temperature overshoot, followed by a return to the temperature goal achieved via net-negative emissions in the second half of this century. When used to inform near-term (e.g., 2030) corporate targets, the result is a set of targets that are aligned with an overshoot of a temperature target, with no explicit long-term commitment to using negative emissions technologies to reverse this. To decrease the risk of this misalignment with the long-term temperature goal, we propose an alternative approach that derives corporate targets directly from the remaining global cumulative carbon budget. We illustrate this approach using global Scope 1 emissions disclosed by public firms in 2019 to estimate corporate carbon budgets and construct idealized emissions-reduction pathways that are consistent with the remaining global carbon budget for 1.5°C and well-below 2°C. While firms, or their sectors, may choose varying mitigation pathways aligned with either global temperature limit, consistency with remaining carbon budgets requires that any delayed mitigation action in the near term is followed by more rapid emissions reductions in subsequent years. This study emphasizes the need for a more precautionary and robust approach to corporate target setting.

Cost-effectiveness analysis, the most common type of economic evaluation, estimates a new option's additional outcome in relation to its extra costs. This is crucial to study within the clinical setting because funding for new treatments and interventions is often linked to whether there is evidence showing they are a good use of resources. This article describes how to analyze a cost-effectiveness dataset using the framework of a net benefit regression. The process of creating estimates and characterizing uncertainty is demonstrated using a hypothetical dataset. The results are explained and illustrated using graphs commonly employed in cost-effectiveness analyses. We conclude with a call to action for researchers to do more person-level cost-effectiveness analysis to produce evidence of the value of new treatments and interventions. Researchers can utilize cost-effectiveness analysis to compare new and existing treatment mechanisms.

Background: Novel, non-invasive diagnostic biomarkers that facilitate early intervention in head and neck cancer are urgently needed. Polyamine metabolites have been observed to be elevated in numerous cancer types and correlated with poor prognosis. The aim of this study was to assess the concentration of polyamines in the saliva and urine from head and neck cancer (HNC) patients, compared to healthy controls. Methods: Targeted metabolomic analysis was performed on saliva and urine from 39 HNC patient samples and compared to 89 healthy controls using a quantitative, targeted liquid chromatography mass spectrometry approach. Results: The metabolites N1-acetylspermine (ASP), N8-acetylspermidine (ASD) and N1,N12-diacetylspermine (DAS) were detected at significantly different concentrations in the urine of HNC patients as compared to healthy controls. Only ASP was detected at elevated levels in HNC saliva as compared to healthy controls. Conclusion: These data suggest that assessment of polyamine-based metabolite biomarkers within the saliva and urine warrants further investigation as a potential diagnostic in HNC patients.

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in MacKenzie, S., Neveu, M., Davila, A., Lunine, J., Cable, M., Phillips-Lander, C., Eigenbrode, J., Waite, J., Craft, K., Hofgartner, J., McKay, C., Glein, C., Burton, D., Kounaves, S., Mathies, R., Vance, S., Malaska, M., Gold, R., German, C., Soderlund, K. M., Willis, P., Freissinet, C., McEwen, A. S., Brucato, J. R., de Vera, J-P. P., Hoehler, T. M., Heldmann, J. Science objectives for flagship-class mission concepts for the search for evidence of life at Enceladus. Astrobiology, 22(6), (2022): 685-712. https://doi.org/10.1089/ast.2020.2425., Cassini revealed that Saturn's Moon Enceladus hosts a subsurface ocean that meets the accepted criteria for habitability with bio-essential elements and compounds, liquid water, and energy sources available in the environment. Whether these conditions are sufficiently abundant and collocated to support life remains unknown and cannot be determined from Cassini data. However, thanks to the plume of oceanic material emanating from Enceladus’ south pole, a new mission to Enceladus could search for evidence of life without having to descend through kilometers of ice. In this article, we outline the science motivations for such a successor to Cassini, choosing the primary science goal to be determining whether Enceladus is inhabited and assuming a resource level equivalent to NASA's Flagship-class missions. We selected a set of potential biosignature measurements that are complementary and orthogonal to build a robust case for any life detection result. This result would be further informed by quantifications of the habitability of the environment through geochemical and geophysical investigations into the ocean and ice shell crust. This study demonstrates that Enceladus’ plume offers an unparalleled opportunity for in situ exploration of an Ocean World and that the planetary science and astrobiology community is well equipped to take full advantage of it in the coming decades., This work was supported by grant 80NSSC20K0136 of the NASA Planetary Mission Concept Studies Program. Some of the research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). C.R.G. acknowledges support from the Exploring Ocean Worlds (ExOW) project (NASA Award: 80NSSC19K1427).

Healthcare facilities are among the most expensive buildings to construct, maintain, and operate. How building design can best support healthcare services, staff, and patients is important to consider. In this narrative review, we outline why the healthcare environment matters and describe areas of research focus and current built environment evidence that supports healthcare in general and stroke care in particular. Ward configuration, corridor design, and staff station placements can all impact care provision, staff and patient behavior. Contrary to many new ward design approaches, single-bed rooms are neither uniformly favored, nor strongly evidence-based, for people with stroke. Green spaces are important both for staff (helping to reduce stress and errors), patients and relatives, although access to, and awareness of, these and other communal spaces is often poor. Built environment research specific to stroke is limited but increasing, and we highlight emerging collaborative multistakeholder partnerships (Living Labs) contributing to this evidence base. We believe that involving engaged and informed clinicians in design and research will help shape better hospitals of the future.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Author Posting. © American Meteorological Society, 2021. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 102(10), (2021): E1936–E1951, https://doi.org/10.1175/BAMS-D-20-0113.1., In the Bay of Bengal, the warm, dry boreal spring concludes with the onset of the summer monsoon and accompanying southwesterly winds, heavy rains, and variable air–sea fluxes. Here, we summarize the 2018 monsoon onset using observations collected through the multinational Monsoon Intraseasonal Oscillations in the Bay of Bengal (MISO-BoB) program between the United States, India, and Sri Lanka. MISO-BoB aims to improve understanding of monsoon intraseasonal variability, and the 2018 field effort captured the coupled air–sea response during a transition from active-to-break conditions in the central BoB. The active phase of the ∼20-day research cruise was characterized by warm sea surface temperature (SST > 30°C), cold atmospheric outflows with intermittent heavy rainfall, and increasing winds (from 2 to 15 m s−1). Accumulated rainfall exceeded 200 mm with 90% of precipitation occurring during the first week. The following break period was both dry and clear, with persistent 10–12 m s−1 wind and evaporation of 0.2 mm h−1. The evolving environmental state included a deepening ocean mixed layer (from ∼20 to 50 m), cooling SST (by ∼1°C), and warming/drying of the lower to midtroposphere. Local atmospheric development was consistent with phasing of the large-scale intraseasonal oscillation. The upper ocean stores significant heat in the BoB, enough to maintain SST above 29°C despite cooling by surface fluxes and ocean mixing. Comparison with reanalysis indicates biases in air–sea fluxes, which may be related to overly cool prescribed SST. Resolution of such biases offers a path toward improved forecasting of transition periods in the monsoon., This work was supported through the U.S. Office of Naval Research’s Departmental Research Initiative: Monsoon Intraseasonal Oscillations in the Bay of Bengal, the Indian Ministry of Earth Science’s Ocean Mixing and Monsoons Program, and the Sri Lankan National Aquatic Resources Research and Development Agency. We thank the Captain and crew of the R/V Thompson for their help in data collection. Surface atmospheric fields included fluxes were quality controlled and processed by the Boundary Layer Observations and Processes Team within the NOAA Physical Sciences Laboratory. Forecast analysis was completed by India Meteorological Department. Drone image was taken by Shreyas Kamat with annotations by Gualtiero Spiro Jaeger. We also recognize the numerous researchers who supported cruise- and land-based measurements. This work represents Lamont-Doherty Earth Observatory contribution number 8503, and PMEL contribution number 5193., 2022-04-01

Dataset: Dissolved trace metal (Mn, Fe, Co, Ni, Cu, Zn, Cd, Pb) concentration, Concentrations of dissolved (<0.2 µm) manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd), lead (Pb) in surface (~2 m) samples collected between 15 August 2018 and 6 September 2018 during EXports Processes in the Oceans from RemoTe Sensing (EXPORTS) cruise aboard RV Roger Revelle RR1813 at Ocean Station PAPA (Station P). For a complete list of measurements, refer to the full dataset description in the supplemental file 'Dataset_description.pdf'. The most current version of this dataset is available at: https://www.bco-dmo.org/dataset/869683, NSF Division of Ocean Sciences (NSF OCE) OCE-1756816, NSF Division of Ocean Sciences (NSF OCE) OCE-1756433, NSF Division of Ocean Sciences (NSF OCE) OCE-1756442

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

The degree to which COVID-19 has disrupted the advances in reducing new HIV infections and preventing AIDS-related deaths is unknown. We present findings related to the effect COVID-19 had on HIV, sexual health and harm reduction service delivery in the state of California. We conducted a qualitative rapid assessment with health care providers, as well as representatives from non-medical support service agencies serving clients living with HIV in a range of counties in California. Some organizations adapted fairly easily while others struggled or were unable to adapt at all. Clinics were better positioned than community-based organizations to accommodate COVID restrictions and to quickly reestablish services. Influential forces that softened or calcified the hardships created by COVID-19 included influx of funding, flexibility in managing funds, networking and relationships, and workforce vulnerabilities. These data clearly suggest that an enhanced level of flexibility within funding streams and reporting requirements should be continued.

In response to ESA’s “Voyage 2050” announcement of opportunity, we propose an ambitious L-class mission to explore one of the most exciting bodies in the Solar System, Saturn’s largest moon Titan. Titan, a “world with two oceans”, is an organic-rich body with interior-surface-atmosphere interactions that are comparable in complexity to the Earth. Titan is also one of the few places in the Solar System with habitability potential. Titan’s remarkable nature was only partly revealed by the Cassini-Huygens mission and still holds mysteries requiring a complete exploration using a variety of vehicles and instruments. The proposed mission concept POSEIDON (Titan POlar Scout/orbitEr and In situ lake lander DrONe explorer) would perform joint orbital and in situ investigations of Titan. It is designed to build on and exceed the scope and scientific/technological accomplishments of Cassini-Huygens, exploring Titan in ways that were not previously possible, in particular through full close-up and in situ coverage over long periods of time. In the proposed mission architecture, POSEIDON consists of two major elements: a spacecraft with a large set of instruments that would orbit Titan, preferably in a low-eccentricity polar orbit, and a suite of in situ investigation components, i.e. a lake lander, a “heavy” drone (possibly amphibious) and/or a fleet of mini-drones, dedicated to the exploration of the polar regions. The ideal arrival time at Titan would be slightly before the next northern Spring equinox (2039), as equinoxes are the most active periods to monitor still largely unknown atmospheric and surface seasonal changes. The exploration of Titan’s northern latitudes with an orbiter and in situ element(s) would be highly complementary in terms of timing (with possible mission timing overlap), locations, and science goals with the upcoming NASA New Frontiers Dragonfly mission that will provide in situ exploration of Titan’s equatorial regions, in the mid-2030s.

Objective: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide. Background: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience. Methods: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie. Results: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%). Conclusion: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.

The Simons Observatory is a ground-based cosmic microwave background instrument to be sited in the Atacama Desert in Chile. SO will deploy 60,000 transition-edge sensors (TES) bolometers in 49 separate focal-plane modules across a suite of four telescopes covering three dichroic bands termed low frequency (LF), mid-frequency and ultra-high frequency. Each MF and UHF focal-plane module packages 1720 feedhorn-coupled detectors with cryogenic components for highly multiplexed readout using microwave SQUID multiplexing. In this paper, we describe the testing program we have developed for high-throughput validation of modules after they are assembled. The validation requires measurements of the yield, saturation powers, time constants, noise properties and optical efficiencies. Additional measurements will be performed for further characterization as needed. We describe the methods developed and demonstrate preliminary results from the initial testing of a prototype module.

First published online July 15, 2022, Despite the tangible progress in psychological and cognitive sciences over the last several years, these disciplines still trail other more mature sciences in identifying the most important questions that need to be solved. Reaching such consensus could lead to greater synergy across different laboratories, faster progress, and increased focus on solving important problems rather than pursuing isolated, niche efforts. Here, 26 researchers from the field of visual metacognition reached consensus on four long-term and two medium-term common goals. We describe the process that we followed, the goals themselves, and our plans for accomplishing these goals. If this effort proves successful within the next few years, such consensus building around common goals could be adopted more widely in psychological science.

Background: Critically ill adults are at increased risk of VTE, including DVT, and pulmonary embolism. Various agents exist for venous thromboprophylaxis in this population. Research Question: What is the comparative efficacy and safety of prophylaxis agents for prevention of VTE in critically ill adults? Study Design and Methods: Systematic review and network meta-analysis of randomized clinical trials (RCTs) evaluating efficacy of thromboprophylaxis agents among critically ill patients. We searched six databases (including PubMed, EMBASE, and Medline) from inception through January 2021 for RCTs of patients in the ICU receiving pharmacologic, mechanical, or combination therapy (pharmacologic agents and mechanical devices) for thromboprophylaxis. Two reviewers performed screening, full-text review, and extraction. We used the Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. Results: We included 13 RCTs (9,619 patients). Compared with control treatment (a composite of no prophylaxis, placebo, or compression stockings only), low-molecular-weight heparin (LMWH) reduced the incidence of DVT (OR, 0.59 [95% credible interval [CrI], 0.33-0.90]; high certainty) and unfractionated heparin (UFH) may reduce the incidence of DVT (OR, 0.82 [95% CrI, 0.47-1.37]; low certainty). LMWH probably reduces DVT compared with UFH (OR, 0.72 [95% CrI, 0.46-0.98]; moderate certainty). Compressive devices may reduce risk of DVT compared with control treatments; however, this is based on low-certainty evidence (OR, 0.85 [95% CrI, 0.50-1.50]). Combination therapy showed unclear effect on DVT compared with either therapy alone (very low certainty). Interpretation: Among critically ill adults, compared with control treatment, LMWH reduces incidence of DVT, whereas UFH and mechanical compressive devices may reduce the risk of DVT. LMWH is probably more effective than UFH in reducing incidence of DVT and should be considered the primary p

Women are underrepresented in many aviation occupations despite outreach and recruitment efforts from multiple organizations. Attracting women into aviation is a necessity not only to address workforce demand but also to achieve the benefits of a more diverse workforce to include enhanced profitability, safety, and innovation. To address the gender gap, the research presented here attempts to inform recruitment/retention strategies by identifying both the positive and negative factors that influence a woman’s decision to pursue a career in aviation and the decision to persist. Additionally, factors such as participation in youth outreach programs, role of mentors, influencers who support or interfere with the pursuit of aviation as a career for women, and development of a better understanding of barriers to the career field are all explored. The results reveal a profile for recruiting, and identification of factors that deter women from the field, which include cost of entry, negative workplace culture, and maintaining work life balance. The information gained will allow for tailoring strategies for the recruitment, retention, and advancement of women to the identified factors that influence career decisions in order to close the existing gender gaps in aviation.

LiteBIRD is a JAXA-led strategic large-class satellite mission designed to measure the polarization of the cosmic microwave background and Galactic foregrounds from 34 to 448 GHz across the entire sky from L2 in the late 2020s. The scientific payload includes three telescopes which are called the low-, mid-, and high-frequency telescopes each with their own receiver that covers a portion of the mission's frequency range. The low frequency telescope will map synchrotron radiation from the Galactic foreground and the cosmic microwave background. We discuss the design, fabrication, and characterization of the low-frequency focal plane modules for low-frequency telescope, which has a total bandwidth ranging from 34 to 161 GHz. There will be a total of 4 different pixel types with 8 overlapping bands to cover the full frequency range. These modules are housed in a single low-frequency focal plane unit which provides thermal isolation, mechanical support, and radiative baffling for the detectors. The module design implements multi-chroic lenslet-coupled sinuous antenna arrays coupled to transition edge sensor bolometers read out with frequency-domain mulitplexing. While this technology has strong heritage in ground-based cosmic microwave background experiments, the broad frequency coverage, low optical loading conditions, and the high cosmic ray background of the space environment require further development of this technology to be suitable for LiteBIRD. In these proceedings, we discuss the optical and bolometeric characterization of a triplexing prototype pixel with bands centered on 78, 100, and 140 GHz., Comment: SPIE Astronomical Telescope + Instrumentation (AS22)