Magnetic Polarity Stratigraphy and \u3csup\u3e40\u3c/sup\u3eK-\u3csup\u3e40\u3c/sup\u3eAR Dating of Late Miocene and Early Pliocene Continental Deposits, Catamarca Province, NW Argentina

Magnetostratigraphic and 40K-40Ar data on a 2300 m thick sequence of continental sediments at Puerta de Corral Quemado in Catamarca Province, NW Argentina permit calibration of land mammal faunas of late Tertiary (Huayquerian and Montehermosan) age. The sequence represents (from oldest to youngest) the Chiquimil A, Araucanense, and Corral Quemado Formations. Paleomagnetic samples were collected from 99 stratigraphic levels. Strong-field thermomagnetic and isothermal remanent magnetization experiments indicate that the dominant ferrimagnetic mineral is magnetite. Progressive alternating-field (AF) and themal demagnetization of the natural remanent magnetism (NRM) demonstrates that AF demagnetization to 20 mT peak field is sufficient to isolate the primary NRM which is of depositional origin. The resulting paleomagnetic data provide a well-defined magnetic polarity zonation, although sampling is less dense in the upper half of the section. 40K-40Ar data obtained from mineral separates of four tuffs within the section allow reliable age determinations for those levels. The combined magnetostratigraphic and 40K-40Ar data allow the magnetic polarity zonation to be correlated with the magnetic polarity time scale. This correlation indicates a nearly constant rate of sediment accumulation between ~8.0 Ma and 3.5 Ma. The boundary between the Araucanense and Corral Quemado Formations approximates the boundary between the Huayquerian and Montehermosan land mammal age faunas at this locality. The data presented here allow the boundary between the Araucanense and Corral Quemado Formations to be dated at 6.4 Ma. Combined with geochronologic data from similar age rocks and faunas from San Carlos, Mendoza Province, west-central Argentina, the geochronologic data from Puerta de Corral Quemado allow the Huayquerian-Monteher-mosan land mammal age boundary to be placed tentatively at 6.0 Ma. A specimen of the fossil land mammal Cyonasua (family Procyonidae) from unit 14 of the Araucanense Formation is dated at 7.0 to 7.5 Ma. This specimen is the earliest known representative of this North American group in South America and represents the oldest dated participant in the Great American Faunal Interchange on that continent

Geochronology of Type Santacrucian (Middle Tertiary) Land Mammal Age, Patagonia, Argentina

Mammal-bearing lacustrine and tuffaceous sediments from three localities of the Santa Cruz Formation, type fauna of the Santacrucian Land Mammal Age, in Patagonia, southern Argentina, are calibrated by radioisotope dating with the aid of magnetostratigraphy. The strata range from about 17.6 Ma to perhaps 16.0 Ma, and are thus of late-early Miocene age. The Santacrucian Land Mammal Age ranges from about 18.0 Ma to about 15.0 Ma

Cause of Death in Patients With Acute Heart Failure: Insights From RELAX-AHF-2

OBJECTIVES: This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial. BACKGROUND: Patients with AHF continue to suffer significant short-term mortality, but limited systematic analyses of causes of death in this patient population are available. METHODS: Adjudicated cause of death of patients in RELAX-AHF-2, a randomized, double-blind, placebo-controlled trial of serelaxin in patients with AHF across the spectrum of ejection fraction (EF), was analyzed. RESULTS: By 180 days of follow-up, 11.5% of patients in RELAX-AHF-2 died, primarily due to heart failure (HF) (38% of all deaths). Unlike RELAX-AHF, there was no apparent effect of treatment with serelaxin on any category of cause of death. Older patients (≥75 years) had higher rates of mortality (14.2% vs. 8.8%) and noncardiovascular (CV) death (27% vs. 19%) compared to younger patients. Patients with preserved EF (≥50%) had lower rates of HF-related mortality (30% vs. 40%) but higher non-CV mortality (36% vs. 20%) compared to patients with reduced EF. CONCLUSIONS: Despite previous data suggesting benefit of serelaxin in AHF, treatment with serelaxin was not found to improve overall mortality or have an effect on any category of cause of death in RELAX-AHF-2. Careful adjudication of events in the serelaxin trials showed that older patients and those with preserved EF had fewer deaths from HF or sudden death and more deaths from other CV causes and from noncardiac causes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778)

Cause of Death in Patients With Acute Heart Failure Insights From RELAX-AHF-2

OBJECTIVES: This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial. BACKGROUND: Patients with AHF continue to suffer significant short-term mortality, but limited systematic analyses of causes of death in this patient population are available. METHODS: Adjudicated cause of death of patients in RELAX-AHF-2, a randomized, double-blind, placebo-controlled trial of serelaxin in patients with AHF across the spectrum of ejection fraction (EF), was analyzed. RESULTS: By 180 days of follow-up, 11.5% of patients in RELAX-AHF-2 died, primarily due to heart failure (HF) (38% of all deaths). Unlike RELAX-AHF, there was no apparent effect of treatment with serelaxin on any category of cause of death. Older patients (≥75 years) had higher rates of mortality (14.2% vs. 8.8%) and noncardiovascular (CV) death (27% vs. 19%) compared to younger patients. Patients with preserved EF (≥50%) had lower rates of HF-related mortality (30% vs. 40%) but higher non-CV mortality (36% vs. 20%) compared to patients with reduced EF. CONCLUSIONS: Despite previous data suggesting benefit of serelaxin in AHF, treatment with serelaxin was not found to improve overall mortality or have an effect on any category of cause of death in RELAX-AHF-2. Careful adjudication of events in the serelaxin trials showed that older patients and those with preserved EF had fewer deaths from HF or sudden death and more deaths from other CV causes and from noncardiac causes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778)

Effect of a Hospital and Postdischarge Quality Improvement Intervention on Clinical Outcomes and Quality of Care for Patients With Heart Failure With Reduced Ejection Fraction: The CONNECT-HF Randomized Clinical Trial

Importance: Adoption of guideline-directed medical therapy for patients with heart failure is variable. Interventions to improve guideline-directed medical therapy have failed to consistently achieve target metrics, and limited data exist to inform efforts to improve heart failure quality of care. Objective: To evaluate the effect of a hospital and postdischarge quality improvement intervention compared with usual care on heart failure outcomes and care. Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 161 US hospitals and included 5647 patients (2675 intervention vs 2972 usual care) followed up after a hospital discharge for acute heart failure with reduced ejection fraction (HFrEF). The trial was performed from 2017 to 2020, and the date of final follow-up was August 31, 2020. Interventions: Hospitals (n = 82) randomized to a hospital and postdischarge quality improvement intervention received regular education of clinicians by a trained group of heart failure and quality improvement experts and audit and feedback on heart failure process measures (eg, use of guideline-directed medical therapy for HFrEF) and outcomes. Hospitals (n = 79) randomized to usual care received access to a generalized heart failure education website. Main Outcomes and Measures: The coprimary outcomes were a composite of first heart failure rehospitalization or all-cause mortality and change in an opportunity-based composite score for heart failure quality (percentage of recommendations followed). Results: Among 5647 patients (mean age, 63 years; 33% women; 38% Black; 87% chronic heart failure; 49% recent heart failure hospitalization), vital status was known for 5636 (99.8%). Heart failure rehospitalization or all-cause mortality occurred in 38.6% in the intervention group vs 39.2% in usual care (adjusted hazard ratio, 0.92 [95% CI, 0.81 to 1.05). The baseline quality-of-care score was 42.1% vs 45.5%, respectively, and the change from baseline to follow-up was 2.3% vs -1.0% (difference, 3.3% [95% CI, -0.8% to 7.3%]), with no significant difference between the 2 groups in the odds of achieving a higher composite quality score at last follow-up (adjusted odds ratio, 1.06 [95% CI, 0.93 to 1.21]). Conclusions and Relevance: Among patients with HFrEF in hospitals randomized to a hospital and postdischarge quality improvement intervention vs usual care, there was no significant difference in time to first heart failure rehospitalization or death, or in change in a composite heart failure quality-of-care score. Trial Registration: ClinicalTrials.gov Identifier: NCT03035474

Global ozone and air quality: a multi-model assessment of risks to human health and crops

Within ACCENT, a European Network of Excellence, eighteen atmospheric models from the U.S., Europe, and Japan calculated present (2000) and future (2030) concentrations of ozone at the Earth's surface with hourly temporal resolution. Comparison of model results with surface ozone measurements in 14 world regions indicates that levels and seasonality of surface ozone in North America and Europe are characterized well by global models, with annual average biases typically within 5–10 nmol/mol. However, comparison with rather sparse observations over some regions suggest that most models overestimate annual ozone by 15–20 nmol/mol in some locations. Two scenarios from the International Institute for Applied Systems Analysis (IIASA) and one from the Intergovernmental Panel on Climate Change Special Report on Emissions Scenarios (IPCC SRES) have been implemented in the models. This study focuses on changes in near-surface ozone and their effects on human health and vegetation. Different indices and air quality standards are used to characterise air quality. We show that often the calculated changes in the different indices are closely inter-related. Indices using lower thresholds are more consistent between the models, and are recommended for global model analysis. Our analysis indicates that currently about two-thirds of the regions considered do not meet health air quality standards, whereas only 2–4 regions remain below the threshold. Calculated air quality exceedances show moderate deterioration by 2030 if current emissions legislation is followed and slight improvements if current emissions reduction technology is used optimally. For the "business as usual" scenario severe air quality problems are predicted. We show that model simulations of air quality indices are particularly sensitive to how well ozone is represented, and improved accuracy is needed for future projections. Additional measurements are needed to allow a more quantitative assessment of the risks to human health and vegetation from changing levels of surface ozone

Multi-decadal changes in tundra environments and ecosystems: Synthesis of the International Polar Year-Back to the Future Project (IPY-BTF).

Understanding the responses of tundra systems to global change has global implications. Most tundra regions lack sustained environmental monitoring and one of the only ways to document multi-decadal change is to resample historic research sites. The International Polar Year (IPY) provided a unique opportunity for such research through the Back to the Future (BTF) project (IPY project #512). This article synthesizes the results from 13 papers within this Ambio Special Issue. Abiotic changes include glacial recession in the Altai Mountains, Russia; increased snow depth and hardness, permafrost warming, and increased growing season length in sub-arctic Sweden; drying of ponds in Greenland; increased nutrient availability in Alaskan tundra ponds, and warming at most locations studied. Biotic changes ranged from relatively minor plant community change at two sites in Greenland to moderate change in the Yukon, and to dramatic increases in shrub and tree density on Herschel Island, and in sub-arctic Sweden. The population of geese tripled at one site in northeast Greenland where biomass in non-grazed plots doubled. A model parameterized using results from a BTF study forecasts substantial declines in all snowbeds and increases in shrub tundra on Niwot Ridge, Colorado over the next century. In general, results support and provide improved capacities for validating experimental manipulation, remote sensing, and modeling studies

Broadening of Neutralization Activity to Directly Block a Dominant Antibody-Driven SARS-Coronavirus Evolution Pathway

Phylogenetic analyses have provided strong evidence that amino acid changes in spike (S) protein of animal and human SARS coronaviruses (SARS-CoVs) during and between two zoonotic transfers (2002/03 and 2003/04) are the result of positive selection. While several studies support that some amino acid changes between animal and human viruses are the result of inter-species adaptation, the role of neutralizing antibodies (nAbs) in driving SARS-CoV evolution, particularly during intra-species transmission, is unknown. A detailed examination of SARS-CoV infected animal and human convalescent sera could provide evidence of nAb pressure which, if found, may lead to strategies to effectively block virus evolution pathways by broadening the activity of nAbs. Here we show, by focusing on a dominant neutralization epitope, that contemporaneous- and cross-strain nAb responses against SARS-CoV spike protein exist during natural infection. In vitro immune pressure on this epitope using 2002/03 strain-specific nAb 80R recapitulated a dominant escape mutation that was present in all 2003/04 animal and human viruses. Strategies to block this nAb escape/naturally occurring evolution pathway by generating broad nAbs (BnAbs) with activity against 80R escape mutants and both 2002/03 and 2003/04 strains were explored. Structure-based amino acid changes in an activation-induced cytidine deaminase (AID) “hot spot” in a light chain CDR (complementarity determining region) alone, introduced through shuffling of naturally occurring non-immune human VL chain repertoire or by targeted mutagenesis, were successful in generating these BnAbs. These results demonstrate that nAb-mediated immune pressure is likely a driving force for positive selection during intra-species transmission of SARS-CoV. Somatic hypermutation (SHM) of a single VL CDR can markedly broaden the activity of a strain-specific nAb. The strategies investigated in this study, in particular the use of structural information in combination of chain-shuffling as well as hot-spot CDR mutagenesis, can be exploited to broaden neutralization activity, to improve anti-viral nAb therapies, and directly manipulate virus evolution