Barriers to recruiting primary care practices for implementation research during COVID-19: A qualitative study of practice coaches from the Stop Unhealthy (STUN) Alcohol Use Now trial

Background: The COVID-19 pandemic has brought widespread change to health care practice and research. With heightened stress in the general population, increased unhealthy alcohol use, and added pressures on primary care practices, comes the need to better understand how we can continue practice-based research and address public health priorities amid the ongoing pandemic. The current study considers barriers and facilitators to conducting such research, especially during the COVID-19 pandemic, within the context of recruiting practices for the STop UNhealthy (STUN) Alcohol Use Now trial. The STUN trial uses practice facilitation to implement screening and interventions for unhealthy alcohol use in primary care practices across the state of North Carolina. Methods: Semistructured interviews were conducted with a purposive sample of 15 practice coaches to discuss their recruitment experiences before and after recruitment was paused due to the pandemic. An inductive thematic analysis was used to identify themes and subthemes. Results: Pandemic-related barriers, including challenges in staffing, finances, and new COVID-19-related workflows, were most prominent. Competing priorities, such as quality improvement measures, North Carolina's implementation of Medicaid managed care, and organizational structures hampered recruitment efforts. Coaches also described barriers specific to the project and to the topic of alcohol. Several facilitators were identified, including the rising importance of behavioral health due to the pandemic, as well as existing relationships between practice coaches and practices. Conclusions: Difficulty managing competing priorities and obstacles within existing practice infrastructure inhibit the ability to participate in practice-based research and implementation of evidence-based practices. Lessons learned from this trial may inform strategies to recruit practices into research and to gain buy-in from practices in adopting evidence-based practices more generally. Plain Language Summary What is known: Unhealthy alcohol use is a significant public health issue, which has been exacerbated during the COVID-19 pandemic. Screening and brief intervention for unhealthy alcohol use is an evidence-based practice shown to help reduce drinking-related behaviors, yet it remains rare in practice. What this study adds: Using a qualitative approach, we identify barriers and facilitators to recruiting primary care practices into a funded trial that uses practice facilitation to address unhealthy alcohol use. We identify general insights as well as those specific to the COVID-19 pandemic. Barriers are primarily related to competing priorities, incentives, and lack of infrastructure. Facilitators are related to framing of the project and the anticipated level and type of resources needed to address unhealthy alcohol use especially as the pandemic wanes. Implications: Our findings provide information on barriers and facilitators to recruiting primary care practices for behavioral health projects and to implementing these activities. Using our findings, we provide a discussion of suggestions for conducting these types of projects in the future which may be of interest to researchers, practice managers, and providers

Intrauterine growth-restricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term

Intrauterine growthrestricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term. Am J Physiol Regul Integr Comp Physiol 310: R1020–R1029, 2016. First published April 6, 2016; doi:10.1152/ajpregu.00528.2015.—Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fibertype ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers. Placental insufficiency-induced IUGR fetuses were 54% smaller (P \u3c 0.05) than controls and exhibited hypoxemia and hypoglycemia, which contributed to 6.9- fold greater (P \u3c 0.05) plasma norepinephrine and 53% lower (P \u3c 0.05) plasma insulin concentrations. IUGR semitendinosus muscles contained less (P \u3c 0.05) myosin heavy chain-I protein (MyHC-I) and proportionally fewer (P \u3c 0.05) Type I and Type I/IIa fibers than controls, but MyHC-II protein concentrations, Type II fibers, and Type IIx fibers were not different. IUGR biceps femoris muscles exhibited similar albeit less dramatic differences in fiber type proportions. Type I and IIa fibers are more responsive to adrenergic and insulin regulation than Type IIx and may be more profoundly impaired by the high catecholamines and low insulin in our IUGR fetuses, leading to their proportional reduction. In both muscles, fibers of each type were uniformly smaller (P \u3c 0.05) in IUGR fetuses than controls, which indicates that fiber hypertrophy is not dependent on type but rather on other factors such as myoblast differentiation or protein synthesis. Together, our findings show that IUGR fetal muscles develop smaller fibers and have proportionally fewer Type I fibers, which is indicative of developmental adaptations that may help explain the link between IUGR and adulthood insulin resistanc

Flexible Supervised Autonomy for Exploration in Subterranean Environments

While the capabilities of autonomous systems have been steadily improving in recent years, these systems still struggle to rapidly explore previously unknown environments without the aid of GPS-assisted navigation. The DARPA Subterranean (SubT) Challenge aimed to fast track the development of autonomous exploration systems by evaluating their performance in real-world underground search-and-rescue scenarios. Subterranean environments present a plethora of challenges for robotic systems, such as limited communications, complex topology, visually-degraded sensing, and harsh terrain. The presented solution enables long-term autonomy with minimal human supervision by combining a powerful and independent single-agent autonomy stack, with higher level mission management operating over a flexible mesh network. The autonomy suite deployed on quadruped and wheeled robots was fully independent, freeing the human supervision to loosely supervise the mission and make high-impact strategic decisions. We also discuss lessons learned from fielding our system at the SubT Final Event, relating to vehicle versatility, system adaptability, and re-configurable communications.Comment: Field Robotics special issue: DARPA Subterranean Challenge, Advancement and Lessons Learned from the Final

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro)

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for Mpro, including mobile solvent interleaved between the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to counter-punch COVID-19 and combat future coronavirus pandemics

Modeling and characterization of the SPIDER half-wave plate

Spider is a balloon-borne array of six telescopes that will observe the Cosmic Microwave Background. The 2624 antenna-coupled bolometers in the instrument will make a polarization map of the CMB with approximately one-half degree resolution at 145 GHz. Polarization modulation is achieved via a cryogenic sapphire half-wave plate (HWP) skyward of the primary optic. We have measured millimeter-wave transmission spectra of the sapphire at room and cryogenic temperatures. The spectra are consistent with our physical optics model, and the data gives excellent measurements of the indices of A-cut sapphire. We have also taken preliminary spectra of the integrated HWP, optical system, and detectors in the prototype Spider receiver. We calculate the variation in response of the HWP between observing the CMB and foreground spectra, and estimate that it should not limit the Spider constraints on inflation

MAXI and NuSTAR observations of the faint X-ray transient MAXI J1848-015 in the GLIMPSE-C01 Cluster

We present the results of MAXI monitoring and two NuSTAR observations of the recently discovered faint X-ray transient MAXI J1848-015. Analysis of the MAXI light-curve shows that the source underwent a rapid flux increase beginning on 2020 December 20, followed by a rapid decrease in flux after only $\sim5$ days. NuSTAR observations reveal that the source transitioned from a bright soft state with unabsorbed, bolometric ($0.1$-$100$ keV) flux $F=6.9 \pm 0.1 \times 10^{-10}\,\mathrm{erg\,cm^{-2}\,s^{-1}}$, to a low hard state with flux $F=2.85 \pm 0.04 \times 10^{-10}\,\mathrm{erg\,cm^{-2}\,s^{-1}}$. Given a distance of $3.3$ kpc, inferred via association of the source with the GLIMPSE-C01 cluster, these fluxes correspond to an Eddington fraction of order $10^{-3}$ for an accreting neutron star of mass $M=1.4M_\odot$, or even lower for a more massive accretor. However, the source spectra exhibit strong relativistic reflection features, indicating the presence of an accretion disk which extends close to the accretor, for which we measure a high spin, $a=0.967\pm0.013$. In addition to a change in flux and spectral shape, we find evidence for other changes between the soft and hard states, including moderate disk truncation with the inner disk radius increasing from $R_\mathrm{in}\approx3\,R_\mathrm{g}$ to $R_\mathrm{in}\approx8\,R_\mathrm{g}$, narrow Fe emission whose centroid decreases from $6.8\pm0.1$ keV to $6.3 \pm 0.1$ keV, and an increase in low-frequency ($10^{-3}$-$10^{-1}$ Hz) variability. Due to the high spin we conclude that the source is likely to be a black hole rather than a neutron star, and we discuss physical interpretations of the low apparent luminosity as well as the narrow Fe emission.Comment: 19 pages, 9 figures, 3 tables. Accepted for publication in Ap

Whole genome sequencing to investigate the emergence of clonal complex 23 Neisseria meningitidis serogroup Y disease in the United States

In the United States, serogroup Y, ST-23 clonal complex Neisseria meningitidis was responsible for an increase in meningococcal disease incidence during the 1990s. This increase was accompanied by antigenic shift of three outer membrane proteins, with a decrease in the population that predominated in the early 1990s as a different population emerged later in that decade. To understand factors that may have been responsible for the emergence of serogroup Y disease, we used whole genome pyrosequencing to investigate genetic differences between isolates from early and late N. meningitidis populations, obtained from meningococcal disease cases in Maryland in the 1990s. The genomes of isolates from the early and late populations were highly similar, with 1231 of 1776 shared genes exhibiting 100% amino acid identity and an average πN = 0.0033 and average πS = 0.0216. However, differences were found in predicted proteins that affect pilin structure and antigen profile and in predicted proteins involved in iron acquisition and uptake. The observed changes are consistent with acquisition of new alleles through horizontal gene transfer. Changes in antigen profile due to the genetic differences found in this study likely allowed the late population to emerge due to escape from population immunity. These findings may predict which antigenic factors are important in the cyclic epidemiology of meningococcal disease

The Community Land Model version 5 : description of new features, benchmarking, and impact of forcing uncertainty

The Community Land Model (CLM) is the land component of the Community Earth System Model (CESM) and is used in several global and regional modeling systems. In this paper, we introduce model developments included in CLM version 5 (CLM5), which is the default land component for CESM2. We assess an ensemble of simulations, including prescribed and prognostic vegetation state, multiple forcing data sets, and CLM4, CLM4.5, and CLM5, against a range of metrics including from the International Land Model Benchmarking (ILAMBv2) package. CLM5 includes new and updated processes and parameterizations: (1) dynamic land units, (2) updated parameterizations and structure for hydrology and snow (spatially explicit soil depth, dry surface layer, revised groundwater scheme, revised canopy interception and canopy snow processes, updated fresh snow density, simple firn model, and Model for Scale Adaptive River Transport), (3) plant hydraulics and hydraulic redistribution, (4) revised nitrogen cycling (flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake), (5) global crop model with six crop types and time‐evolving irrigated areas and fertilization rates, (6) updated urban building energy, (7) carbon isotopes, and (8) updated stomatal physiology. New optional features include demographically structured dynamic vegetation model (Functionally Assembled Terrestrial Ecosystem Simulator), ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Conclusive establishment of improvement or degradation of individual variables or metrics is challenged by forcing uncertainty, parametric uncertainty, and model structural complexity, but the multivariate metrics presented here suggest a general broad improvement from CLM4 to CLM5

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL