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Paleoproterozoic massive Cu-Zn±Pb±Au±Ag sulphide deposits metamorphosed to the middle-upper amphibolite facies in central-south Colorado formed in a volcanic arc setting on the edge of the Yavapai crustal province. Previously published U-Pb ages on spatially related granitoids range from ∼1.9 to ∼1.1 Ga, while Pb isotope studies on galena from massive sulphides suggest mineralization formed at around 1.8–1.7 Ga. Some deposits in the Dawson-Green Mountain trend (DGMT) and the Gunnison belt are composed of Cu-Zn-Au-(Pb-Ag) mineralization that were overprinted by later Au-(Ag-Cu-Bi-Se-Te) mineralization. Sulphide mineralization is spatially related to amphibolite and bimodal, mafic-felsic volcanic rocks (gabbro, amphibolite, rhyolite and dacite) and granitoids, but it occurs mostly in biotite-garnet-quartz±sillimanite±cordierite schists and gneisses, spatially related to nodular sillimanite rocks, and in some locations, exhalative rocks (iron formations, gahnite-rich rocks and quartz-garnetite). The major metallic minerals of the massive sulphides include chalcopyrite, sphalerite, pyrite, pyrrhotite, and magnetite, with minor galena and gahnite. Altered rocks intimately associated with mineralization primarily consist of various amphiboles (gedrite, tremolite and hornblende), gahnite, biotite, garnet, cordierite, carbonate and rare högbomite. The Zn/Cd ratios of sphalerite (44 to 307) in deposits in the DGMT fall within the range of global volcanogenic massive sulphide (VMS) deposits but overlap with sphalerite from sedimentary exhalative (Sedex) deposits. Sulphur isotope values of sulphides (δ34S = −3.3 to +6.5) suggest sulphur was largely derived from magmatic sources, and that variations in isotopic values resulting from thermochemical sulphate reduction are due to small differences in physicochemical conditions. The preferred genetic model is for the deposits to be bimodal-mafic (Gunnison) to mafic-siliciclastic VMS deposits (Cotopaxi, Cinderella-Bon Ton, DGMT).
Background: Pain in a common symptom in adult-onset idiopathic dystonia (AOID). An appropriate tool to understand this symptom is needed to improve AOID patients’ care. We developed a rating instrument for pain in AOID and validated it in cervical dystonia (CD). Methods: Development and validation of the Pain in Dystonia Scale (PIDS) in three phases: 1. International experts and participants generated and evaluated the preliminary items for content validity; 2. The PIDS was drafted and revised, followed by cognitive interviews to ensure suitability for self-administration; and 3. the clinimetric properties of the final PIDS were assessed in 85 participants. Results: PIDS evaluates pain severity (by body part), functional impact and external modulating factors. It showed high test-retest reliability the total score (0.9, p<0.001), intraclass correlation coefficients higher than 0.7 for all items and high internal consistency (Cronbach’s alpha 0.9). Convergent validity analysis revealed a strong correlation between the PIDS severity score and the TWSTRS pain subscale (0.8, p<0.001), the brief pain inventory short form (0.7, p<0.001) and impact of pain on daily functioning (0.7, p<0.001). Conclusions: The PIDS is the first specific questionnaire developed to evaluate pain in patients with AOID with high-level clinimetric properties in people with CD.
Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body’s natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.
In patients with bipolar disorder, depression symptoms are associated with greater reduction in function and quality of life than hypomania/mania symptoms. Lumateperone (LUMA), is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder.
In a recent phase 3 clinical trial (Study 404, NCT03249376) in people with bipolar depression, LUMA 42 mg monotherapy significantly improved symptoms of depression compared with placebo (PBO). This analysis of Study 404 investigated the effects of LUMA on functional disability and quality of life as measured using the secondary outcome measure, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF).
Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4) were randomized to LUMA 42 mg or PBO orally, once daily in the evening for 6 weeks. The primary endpoint was the change from baseline to Day 43 in MADRS Total score, analyzed using a mixed-effects model for repeated measures (MMRM) approach in the intent-to-treat population (ITT). This post hoc analysis evaluated the mean change from baseline to Day 43 in the Q-LES-Q-SF individual item scores using an analysis of covariance with last observation carried forward (ANCOVA-LOCF) in the ITT. Categorical shifts in individual items were also analyzed.
The ITT comprised 376 patients (LUMA 42 mg, 188; PBO, 188). Patients in the LUMA 42 mg group had significantly greater improvement on MADRS Total score change from baseline to Day 43 compared with PBO (least squares mean difference vs PBO [LSMD], −4.585; 95% CI, −6.344 to −2.826; effect size vs PBO [ES], −0.56; P<.0001). LUMA 42 mg treatment significantly improved Q-LES-Q-SF Total score from baseline to Day 43 compared with PBO (LSMD, 2.9; 95% CI, 1.15 to 4.59; P=.001).
The Q-LES-Q-SF items with the lowest mean scores at baseline in both groups were mood, leisure time activities, and sexual drive, interest, and/or performance. By Day 43, LUMA 42 mg treatment significantly improved 8 of the 14 items in the Q-LES-Q-SF (P<0.05). Overall life satisfaction also significantly improved with LUMA treatment (P=.0016). The largest improvements with LUMA 42 mg compared with PBO (ES>0.3,) were seen for the ability to function in daily life, family relationships, household activities, leisure time activities, and mood (all LSMD=0.3; all P<.01).
In patients with bipolar depression, treatment with LUMA 42 mg compared with PBO significantly improved patient quality of life and functional impairment. These results support LUMA 42 mg as treatment of MDEs associated with bipolar I or bipolar II disorder in adults.
The radio signal transmitted by the Mars Express (MEX) spacecraft was observed regularly between the years 2013–2020 at X-band (8.42 GHz) using the European Very Long Baseline Interferometry (EVN) network and University of Tasmania’s telescopes. We present a method to describe the solar wind parameters by quantifying the effects of plasma on our radio signal. In doing so, we identify all the uncompensated effects on the radio signal and see which coronal processes drive them. From a technical standpoint, quantifying the effect of the plasma on the radio signal helps phase referencing for precision spacecraft tracking. The phase fluctuation of the signal was determined for Mars’ orbit for solar elongation angles from 0 to 180 deg. The calculated phase residuals allow determination of the phase power spectrum. The total electron content of the solar plasma along the line of sight is calculated by removing effects from mechanical and ionospheric noises. The spectral index was determined as $-2.43 \pm 0.11$ which is in agreement with Kolmogorov’s turbulence. The theoretical models are consistent with observations at lower solar elongations however at higher solar elongation ($>$160 deg) we see the observed values to be higher. This can be caused when the uplink and downlink signals are positively correlated as a result of passing through identical plasma sheets.
We present a timeseries of 14CO2 for the period 1910–2021 recorded by annual plants collected in the southwestern United States, centered near Flagstaff, Arizona. This timeseries is dominated by five commonly occurring annual plant species in the region, which is considered broadly representative of the southern Colorado Plateau. Most samples (1910–2015) were previously archived herbarium specimens, with additional samples harvested from field experiments in 2015–2021. We used this novel timeseries to develop a smoothed local record with uncertainties for “bomb spike” 14C dating of recent terrestrial organic matter. Our results highlight the potential importance of local records, as we document a delayed arrival of the 1963–1964 bomb spike peak, lower values in the 1980s, and elevated values in the last decade in comparison to the most current Northern Hemisphere Zone 2 record. It is impossible to retroactively collect atmospheric samples, but archived annual plants serve as faithful scribes: samples from herbaria around the Earth may be an under-utilized resource to improve understanding of the modern carbon cycle.
In recent years, evidence has started piling up that some high-energy cosmic neutrinos can be associated with blazars in flaring states. On 2022 February 26, a new blazar-neutrino coincidence was reported: the track-like neutrino event IC220225A detected by IceCube is spatially coincident with the flat-spectrum radio quasar PKS 0215+015. Like previous associations, this source was found to be in a high optical and γ-ray state. Moreover, the source showed a bright radio outburst, which substantially increases the probability of a true physical association. We have performed six observations with the VLBA shortly after the neutrino event with a monthly cadence and are monitoring the source with the Effelsberg 100m-Telescope, and with the Australia Compact Telescope Array. Here, we present first results on the contemporary parsec-scale jet structure of PKS 0215+015 in total intensity and polarization to constrain possible physical processes leading to neutrino emission in blazars.
We summarize what we assess as the past year's most important findings within climate change research: limits to adaptation, vulnerability hotspots, new threats coming from the climate–health nexus, climate (im)mobility and security, sustainable practices for land use and finance, losses and damages, inclusive societal climate decisions and ways to overcome structural barriers to accelerate mitigation and limit global warming to below 2°C.
We synthesize 10 topics within climate research where there have been significant advances or emerging scientific consensus since January 2021. The selection of these insights was based on input from an international open call with broad disciplinary scope. Findings concern: (1) new aspects of soft and hard limits to adaptation; (2) the emergence of regional vulnerability hotspots from climate impacts and human vulnerability; (3) new threats on the climate–health horizon – some involving plants and animals; (4) climate (im)mobility and the need for anticipatory action; (5) security and climate; (6) sustainable land management as a prerequisite to land-based solutions; (7) sustainable finance practices in the private sector and the need for political guidance; (8) the urgent planetary imperative for addressing losses and damages; (9) inclusive societal choices for climate-resilient development and (10) how to overcome barriers to accelerate mitigation and limit global warming to below 2°C.
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Science has evidence on barriers to mitigation and how to overcome them to avoid limits to adaptation across multiple fields.
To determine the proportion of hospitals that implemented 6 leading practices in their antimicrobial stewardship programs (ASPs). Design: Cross-sectional observational survey.
Advance letters and electronic questionnaires were initiated February 2020. Primary outcomes were percentage of hospitals that (1) implemented facility-specific treatment guidelines (FSTG); (2) performed interactive prospective audit and feedback (PAF) either face-to-face or by telephone; (3) optimized diagnostic testing; (4) measured antibiotic utilization; (5) measured C. difficile infection (CDI); and (6) measured adherence to FSTGs.
Of 948 hospitals invited, 288 (30.4%) completed the questionnaire. Among them, 82 (28.5%) had <99 beds, 162 (56.3%) had 100–399 beds, and 44 (15.2%) had ≥400+ beds. Also, 230 (79.9%) were healthcare system members. Moreover, 161 hospitals (54.8%) reported implementing FSTGs; 214 (72.4%) performed interactive PAF; 105 (34.9%) implemented procedures to optimize diagnostic testing; 235 (79.8%) measured antibiotic utilization; 258 (88.2%) measured CDI; and 110 (37.1%) measured FSTG adherence. Small hospitals performed less interactive PAF (61.0%; P = .0018). Small and nonsystem hospitals were less likely to optimize diagnostic testing: 25.2% (P = .030) and 21.0% (P = .0077), respectively. Small hospitals were less likely to measure antibiotic utilization (67.8%; P = .0010) and CDI (80.3%; P = .0038). Nonsystem hospitals were less likely to implement FSTGs (34.3%; P < .001).
Significant variation exists in the adoption of ASP leading practices. A minority of hospitals have taken action to optimize diagnostic testing and measure adherence to FSTGs. Additional efforts are needed to expand adoption of leading practices across all acute-care hospitals with the greatest need in smaller hospitals.
Background: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a disorder of the elderly with progressive worsening of gait and balance, cognition, and urinary control which requires assessment using criteria recommended by International iNPH guidelines. Methods: Adult Hydrocephalus Clinical Research Network (AHCRN) prospective registry data from 5-centers over a 50-month interval included entry criteria; demographics; comorbidities; examination findings using standard AHCRN gait and neuropsychology assessments; shunt procedures, complications of CSF drainage, complications within 30 days of surgery, and 1-year postoperative follow-up. Results: 547 patients were referred for assessment of suspected-iNPH. 123 patients(21.6%) did not meet clinical criteria to proceed with further testing. 424 patients(74.4%;mean age 76.7 ± 6.0 years;males=269) underwent an LP or lumbar drain, and 193(45.6%) underwent insertion of a ventriculoperitoneal shunt. By 8-12 months after shunt surgery, gait velocity was 0.96±0.35m/s (54% faster than pre-CSF-drainage). Mean MoCA scores increased from 21.0 ± 5.0(median=22.0) at baseline to 22.6±5.5(median=24) 12-months post-surgery. Gait and cognitive improvements were clinically significant. No deaths occurred. 8% of shunt-surgery patients experienced minor complications. The 30-day reoperation rate was 4.1%. Conclusions: This AHCRN study demonstrated that CSF-drainage testing of patients with suspected-iNPH successfully identified those who could undergo CSF-shunt surgery with a high rate of improvement and a low rate of complications.
To examine differences in surgical practices between salaried and fee-for-service (FFS) surgeons for two common degenerative spine conditions. Surgeons may offer different treatments for similar conditions on the basis of their compensation mechanism.
The study assessed the practices of 63 spine surgeons across eight Canadian provinces (39 FFS surgeons and 24 salaried) who performed surgery for two lumbar conditions: stable spinal stenosis and degenerative spondylolisthesis. The study included a multicenter, ambispective review of consecutive spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network registry between October 2012 and July 2018. The primary outcome was the difference in type of procedures performed between the two groups. Secondary study variables included surgical characteristics, baseline patient factors, and patient-reported outcome.
For stable spinal stenosis (n = 2234), salaried surgeons performed statistically fewer uninstrumented fusion (p < 0.05) than FFS surgeons. For degenerative spondylolisthesis (n = 1292), salaried surgeons performed significantly more instrumentation plus interbody fusions (p < 0.05). There were no statistical differences in patient-reported outcomes between the two groups.
Surgeon compensation was associated with different approaches to stable lumbar spinal stenosis and degenerative lumbar spondylolisthesis. Salaried surgeons chose a more conservative approach to spinal stenosis and a more aggressive approach to degenerative spondylolisthesis, which highlights that remuneration is likely a minor determinant in the differences in practice of spinal surgery in Canada. Further research is needed to further elucidate which variables, other than patient demographics and financial incentives, influence surgical decision-making.
As clinical trials were rapidly initiated in response to the COVID-19 pandemic, Data and Safety Monitoring Boards (DSMBs) faced unique challenges overseeing trials of therapies never tested in a disease not yet characterized. Traditionally, individual DSMBs do not interact or have the benefit of seeing data from other accruing trials for an aggregated analysis to meaningfully interpret safety signals of similar therapeutics. In response, we developed a compliant DSMB Coordination (DSMBc) framework to allow the DSMB from one study investigating the use of SARS-CoV-2 convalescent plasma to treat COVID-19 to review data from similar ongoing studies for the purpose of safety monitoring.
The DSMBc process included engagement of DSMB chairs and board members, execution of contractual agreements, secure data acquisition, generation of harmonized reports utilizing statistical graphics, and secure report sharing with DSMB members. Detailed process maps, a secure portal for managing DSMB reports, and templates for data sharing and confidentiality agreements were developed.
Four trials participated. Data from one trial were successfully harmonized with that of an ongoing trial. Harmonized reports allowing for visualization and drill down into the data were presented to the ongoing trial’s DSMB. While DSMB deliberations are confidential, the Chair confirmed successful review of the harmonized report.
It is feasible to coordinate DSMB reviews of multiple independent studies of a similar therapeutic in similar patient cohorts. The materials presented mitigate challenges to DSMBc and will help expand these initiatives so DSMBs may make more informed decisions with all available information.
Gatherings where people are eating and drinking can increase the risk of getting and spreading SARS-CoV-2 among people who are not fully vaccinated; prevention strategies like wearing masks and physical distancing continue to be important for some groups. We conducted an online survey to characterise fall/winter 2020–2021 holiday gatherings, decisions to attend and prevention strategies employed during and before gatherings. We determined associations between practicing prevention strategies, demographics and COVID-19 experience. Among 502 respondents, one-third attended in person holiday gatherings; 73% wore masks and 84% practiced physical distancing, but less did so always (29% and 23%, respectively). Younger adults were 44% more likely to attend gatherings than adults ≥35 years. Younger adults (adjusted prevalence ratio (aPR) 1.53, 95% CI 1.19–1.97), persons who did not experience COVID-19 themselves or have relatives/close friends experience severe COVID-19 (aPR 1.56, 95% CI 1.18–2.07), and non-Hispanic White persons (aPR 1.57, 95% CI 1.13–2.18) were more likely to not always wear masks in public during the 2 weeks before gatherings. Public health messaging emphasizing consistent application of COVID-19 prevention strategies is important to slow the spread of COVID-19.
Background: To describe preliminary results of a multi-center, randomized, blinded, placebo-controlled, pilot trial of shunt surgery in idiopathic normal pressure hydrocephalus (iNPH). Methods: Five sites of the Adult Hydrocephalus Clinical Research Network (AHCRN) randomized 18 patients scheduled for ventriculoperitoneal shunting based on CSF-drainage response. Patients were randomized to a Codman® Certas® Plus valve with SiphonGuard at either setting 4 (Active, N=9) or setting 8/”virtual off” (Placebo, N=9). Patients and assessors were blinded to the shunt setting. Outcomes included 10-meter gait velocity, cognitive function, and bladder activity scores. The prespecified primary analysis compared changes in 4-month gait velocity in the Active versus Placebo groups. Placebo-set shunts were then blindly adjusted to the active setting and all patients underwent 8 and 12-month post-surgical assessment. Results: At 4-months, gait velocity increased by 0.28±0.28m/s in the Active Group and 0.04±0.17m/s in the Placebo Group (p=0.071). Overactive Bladder (OAB-q) scores significantly improved in the Active versus Placebo groups (p=0.007). At 8 months, Placebo gait velocity increased by 0.36±0.27m/s and was comparable to the Active Group (0.40±0.20m/s; p=0.56). Conclusions: This AHCRN study shows a trend suggesting gait velocity improves more at an Active shunt setting than a Placebo shunt setting and demonstrates the feasibility of a placebo-controlled trial in iNPH.
Scanning transmission electron microscopy (STEM) allows for imaging, diffraction, and spectroscopy of materials on length scales ranging from microns to atoms. By using a high-speed, direct electron detector, it is now possible to record a full two-dimensional (2D) image of the diffracted electron beam at each probe position, typically a 2D grid of probe positions. These 4D-STEM datasets are rich in information, including signatures of the local structure, orientation, deformation, electromagnetic fields, and other sample-dependent properties. However, extracting this information requires complex analysis pipelines that include data wrangling, calibration, analysis, and visualization, all while maintaining robustness against imaging distortions and artifacts. In this paper, we present py4DSTEM, an analysis toolkit for measuring material properties from 4D-STEM datasets, written in the Python language and released with an open-source license. We describe the algorithmic steps for dataset calibration and various 4D-STEM property measurements in detail and present results from several experimental datasets. We also implement a simple and universal file format appropriate for electron microscopy data in py4DSTEM, which uses the open-source HDF5 standard. We hope this tool will benefit the research community and help improve the standards for data and computational methods in electron microscopy, and we invite the community to contribute to this ongoing project.
The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.