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Riparian meadows occupy a small proportion of the public lands in the western United States but they provide numerous ecosystem services, including the production of high-quality forage for livestock grazing. Modern conservation management strategies (e.g., reductions in livestock stocking rates and adoption of new riparian grazing standards) have been implemented to better balance riparian conservation and livestock production objectives on publicly managed lands. We examined potential relationships between long-term changes in plant community, livestock grazing pressure and environmental conditions at two spatial scales in meadows grazed under conservation management strategies. Changes in plant community were not associated with either livestock stocking rate or precipitation at the grazing allotment (i.e., administrative) scale. Alternatively, both grazing pressure and precipitation had significant, albeit modest, associations with changes in plant community at the meadow (i.e., ecological site) scale. These results suggest that reductions in stocking rate have improved the balance between riparian conservation and livestock production goals. However, associations between elevation, site wetness, precipitation, and changes in plant community suggest that changing climate conditions (e.g., reduced snowpack and changes in timing of snowmelt) could trigger shifts in plant communities, potentially impacting both conservation and agricultural services (e.g., livestock and forage production). Therefore, adaptive, site-specific management strategies are required to meet grazing pressure limits and safeguard ecosystem services within individual meadows, especially under more variable climate conditions.

Agricultural soils contribute significantly to nitrous oxide (N₂O) emissions, but little data is available on N₂O emissions from smooth bromegrass (Bromus inermis Leyss.) pastures. This study evaluated soil N₂O emissions and herbage accumulation from smooth bromegrass pasture in eastern Nebraska, USA. Nitrous oxide emissions were measured biweekly from March to October in 2011 and 2012 using vented static chambers on smooth bromegrass plots treated with a factorial combination of five urea nitrogen (N) fertilizer rates (0, 45, 90, 135, and 180 kg ha⁻¹) and two ruminant urine treatments (distilled water and urine). Urine input strongly affected daily and cumulative N₂O emissions, but responses to N fertilizer rate depended on growing season rainfall. In 2011, when rainfall was normal, cumulative N₂O emissions increased exponentially with N fertilizer rate. In 2012, drought reduced daily and cumulative N₂O emission responses to N fertilizer rate. Herbage accumulation ranged from 4.46 Mg ha⁻¹ in unfertilized pasture with distilled water to 16.01 Mg ha⁻¹ in pasture with 180 kg N ha⁻¹ and urine in 2011. In 2012, plots treated with urine had 2.2 times more herbage accumulation than plots treated with distilled water but showed no response to N fertilizer rate. Total applied N lost as N₂O ranged from 0–0.6 to 0.5–1.7 % across N fertilizer rates in distilled water and urine treatments, respectively, and thus, support the Intergovernmental Panel on Climate Change default direct emission factors of 1.0 % for N fertilizer additions and 2.0 % for urine excreted by cattle on pasture.

Many wild horse (Equus ferus caballus) populations that inhabit designated federal land in the United States currently exceed management objectives. Overabundant wild horse populations can adversely impact the ecosystem, native wildlife, and other land uses. Unfortunately, there is not a universal solution, as each impacted area may differ ecologically, economically, socially, and politically. Wild horse management is not just a 1-time project but a long-term program where buy-in is needed from the federal and state agencies, local governments, and private partners. Local county governments and private partners can have important insights and significant influence on the development and success of local wild horse management strategies. The combined involvement of local government and stakeholders can have a wide range of benefits including increasing capacity for management, developing new management and placement techniques, and creating authentic program branding and outreach for better placement success. Partners can often complete projects in tighter time frames, find employees, and experience less government red tape in implementation. Buy-in from the local community can also decrease the amount of negative feedback during management implementation and create a support network to counteract the negative aspects of management. Located in the northeast corner of the state of California, USA, Modoc County recognized early on the need for local government participation in conversations and decisions surrounding wild horses and their management on the Devil’s Garden Plateau Wild Horse Territory (WHT). The county implemented a coordinated planning and government-to-government communication process starting in 2011 to engage the Modoc National Forest, which manages the WHT, in meaningful solution-based dialogue. This paper offers examples of unique collaborative opportunities and solutions that have been successfully used in Modoc County to develop and implement a wild horse management plan. In the years since it was adopted, this plan has halted population growth and started to return the population to the appropriate management level on the Devil’s Garden Plateau.

To examine whether continuous glucose monitoring (CGM) with remote monitoring by followers (family/friends) changes glucose management, follower interventions, and health outcomes compared to CGM alone in pregnant women with diabetes. We prospectively stratified first trimester pregnant women with Type 1 Diabetes to CGM Share (remote monitoring) or CGM Alone. We enrolled a main follower per woman. We retrospectively acquired data for pregnant women who did not use CGM (no CGM). We compared hemoglobin A1c (HbA1c) between groups. We compared sensor glucose, follower interventions, and gestational outcomes between CGM Alone and CGM Share. Longitudinal mixed effects models were used for analyses of changes in outcomes over time. HbA1c decreased in all groups throughout pregnancy and was significantly lower over time in women using CGM Share (n = 15) compared to CGM Alone (n = 13) or no CGM (n = 8) (p = 0.0042). CGM Share users had lower median sensor glucose levels (p = 0.0331) and percent time spent >180 mg/dL (p = 0.0228) across pregnancy. There were no significant differences in maternal and fetal outcomes between groups. CGM Share followers had more alerts for hypoglycemia, but did fewer interventions. In this small pilot study, use of CGM with remote monitoring improved some glycemic metrics in pregnant women with diabetes.

Clinical prediction models estimate an individual’s risk (probability) of a health related outcome to help guide patient counselling and clinical decision making. Most models provide a single point estimate of risk but without the associated uncertainty. Riley and colleagues argue that this needs to change, as understanding uncertainty of risk estimates helps to inform critical evaluation of a model and may impact shared decision making. Examples are provided to illustrate uncertainty in risk estimates, and key methods to quantify and present uncertainty are discussed.

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody 1 . Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab 2 , S2X259 3 and S2H97 4 . The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers. Pseudovirus assays and surface plasmon resonance show that the Omicron receptor-binding domain binds to human ACE2 with increased affinity relative to the ancestral virus, and that most neutralizing antibodies are considerably less potent against Omicron.

SummaryWe evaluated trabecular bone score (TBS) and factors affecting TBS in adults with type 1 diabetes (T1D) compared to age-, sex-, and body mass index (BMI)-matched adults without diabetes. Adults with T1D had lower TBS compared to controls. Abdominal obesity and insulin resistance are associated with lower TBS.IntroductionWe evaluated TBS, a non-invasive method to evaluate trabecular bone quality at the lumbar spine, in adults with T1D compared to age-, sex-, and BMI-matched adults without diabetes.MethodsWe calculated TBS from adults with T1D (n = 47) and controls (n = 47) who had a lumbar spine dual x-ray absorptiometry (DXA) at their third visit (2006–2009) of the ongoing “Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.” The linear relationships of TBS and bone mineral density (BMD) with hemoglobin A1c, blood pressure, lipids, and insulin resistance were evaluated using Pearson’s correlation coefficient. Multiple linear regression was used to test the association of TBS with sex and diabetes while adjusting for other potential confounders.ResultsTBS was significantly lower in adults with T1D compared to controls (1.42 ± 0.12 vs 1.44 ± 0.08, p = 0.02) after adjusting for age, sex, current smoking status, and lumbar spine BMD, despite no difference in lumbar spine BMD between the groups. Components of the metabolic syndrome, including diastolic blood pressure, BMI, triglycerides, and insulin resistance were negatively correlated with TBS among patients with T1D.ConclusionTrabecular bone score, an indirect measurement of trabecular bone quality, was lower in adults with T1D compared to controls. Components of metabolic syndrome and insulin resistance were associated with lower TBS in adults with T1D.

IntroductionEwing sarcoma is a rare paediatric cancer. Currently, there is no way of accurately predicting these patients’ survival at diagnosis. Disease type (ie, localised disease, lung/pleuropulmonary metastases and other metastases) is used to guide treatment decisions, with metastatic patients generally having worse outcomes than localised disease patients. However, not all patients fit this trend. An accurate prognostic model could be used to guide treatment decisions in clinical practice to avoid patients being incorrectly under or overtreated.Methods and analysisThis study aims to develop and internally validate prognostic models in newly diagnosed Ewing sarcoma patients, using the EE2012 clinical trial data set. The models will incorporate prognostic factors, identified from a literature review, to predict patients’ probability of event-free survival at clinically important time points. Three models will be developed, for comparison of their performance and stability, using different methods of model selection and penalisation for overfitting (full model or backwards selection applying uniform shrinkage; and lasso variable selection). The models will be internally validated using bootstrapping to give optimism-adjusted performance statistics (calibration and discrimination) and model stability results. Patient and clinical user groups will be asked to determine risk thresholds to guide treatment decisions in clinical practice based on the model. Decision curve analyses will examine clinical utility at these thresholds.Ethics and disseminationThis study is a secondary analysis of EE2012 clinical trial data. The EE2012 trial received ethical approval from the competent authorities (UK ethics reference approval number 12/NW/0827). This study is covered by the trial ethics in place. The results from this study will be published in peer-reviewed journals to act as a benchmark for future studies.Trial registration numberEudraCT number 2012-002107-17. ISRCTN number 92192408.

Studies in the mouse demonstrate the importance of fibroblast growth factor (FGF) and extra-cellular receptor tyrosine kinase (ERK) in specification of embryo-fated epiblast and yolk-sac-fated hypoblast cells from uncommitted inner cell mass (ICM) cells prior to implantation. Molecular mechanisms regulating specification of early lineages in human development are comparatively unclear. Here we show that exogenous FGF stimulation leads to expanded hypoblast molecular marker expression, at the expense of the epiblast. Conversely, we show that specifically inhibiting ERK activity leads to expansion of epiblast cells functionally capable of giving rise to naïve human pluripotent stem cells. Single-cell transcriptomic analysis indicates that these epiblast cells downregulate FGF signalling and maintain molecular markers of the epiblast. Our functional study demonstrates the molecular mechanisms governing ICM specification in human development, whereby segregation of the epiblast and hypoblast lineages occurs during maturation of the mammalian embryo in an ERK signal-dependent manner. The authors show human embryo lineage specification in the blastocyst is driven by differential FGF/ERK signaling, which segregates yolk sac-fated hypoblast and embryonic epiblast. They establish naïve embryonic stem cells based on these insights.

The recent emergence of SARS-CoV-2 variants of concern 1 – 10 and the recurrent spillovers of coronaviruses 11 , 12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters ( Mesocricetus auratus ) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses. The human monoclonal antibody S2X259 cross-reacts with spike proteins from all clades of sarbecovirus, and provides prophylactic and therapeutic protection in vivo against parental SARS-CoV-2 and emerging variants of concern.