The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important ...part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
While there is strong evidence supporting the importance of telemedicine in stroke, its role in other areas of neurology is not as clear. The goal of this review is to provide an overview of ...evidence-based data on the role of teleneurology in the care of patients with neurologic disorders other than stroke.
Studies across multiple specialties report noninferiority of evaluations by telemedicine compared with traditional, in-person evaluations in terms of patient and caregiver satisfaction. Evidence reports benefits in expediting care, increasing access, reducing cost, and improving diagnostic accuracy and health outcomes. However, many studies are limited, and gaps in knowledge remain.
Telemedicine use is expanding across the vast array of neurologic disorders. More studies are needed to validate and support its use.
Long-term perspective on wildfires in the western USA Marlon, Jennifer R; Bartlein, Patrick J; Gavin, Daniel G ...
Proceedings of the National Academy of Sciences,
02/2012, Letnik:
109, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Understanding the causes and consequences of wildfires in forests of the western United States requires integrated information about fire, climate changes, and human activity on multiple temporal ...scales. We use sedimentary charcoal accumulation rates to construct long-term variations in fire during the past 3,000 y in the American West and compare this record to independent fire-history data from historical records and fire scars. There has been a slight decline in burning over the past 3,000 y, with the lowest levels attained during the 20th century and during the Little Ice Age (LIA, ca. 1400–1700 CE Common Era). Prominent peaks in forest fires occurred during the Medieval Climate Anomaly (ca. 950–1250 CE) and during the 1800s. Analysis of climate reconstructions beginning from 500 CE and population data show that temperature and drought predict changes in biomass burning up to the late 1800s CE. Since the late 1800s , human activities and the ecological effects of recent high fire activity caused a large, abrupt decline in burning similar to the LIA fire decline. Consequently, there is now a forest "fire deficit" in the western United States attributable to the combined effects of human activities, ecological, and climate changes. Large fires in the late 20th and 21st century fires have begun to address the fire deficit, but it is continuing to grow.
Bird-building collisions are the largest source of avian collision mortality in North America. Despite a growing literature on bird-building collisions, little research has been conducted in downtown ...areas of major cities, and no studies have included stadiums, which can be extremely large, often have extensive glass surfaces and lighting, and therefore may cause many bird collisions. Further, few studies have assessed the role of nighttime lighting in increasing collisions, despite the often-cited importance of this factor, or considered collision correlates for different seasons and bird species. We conducted bird collision monitoring over four migration seasons at 21 buildings, including a large multi-use stadium, in downtown Minneapolis, Minnesota, USA. We used a rigorous survey methodology to quantify among-building variation in collisions and assess how building features (e.g., glass area, lighting, vegetation) influence total collision fatalities, fatalities for separate seasons and species, and numbers of species colliding. Four buildings, including the stadium, caused a high proportion of all collisions and drove positive effects of glass area and amount of surrounding vegetation on most collision variables. Excluding these buildings from analyses resulted in slightly different collision predictors, suggesting that factors leading some buildings to cause high numbers of collisions are not the exact same factors causing variation among more typical buildings. We also found variation in collision correlates between spring and fall migration and among bird species, that factors influencing collision fatalities also influence numbers of species colliding, and that the proportion, and potentially area, of glass lighted at night are associated with collisions. Thus, reducing bird collisions at large buildings, including stadiums, should be achievable by reducing glass area (or treating existing glass), reducing light emission at night, and prioritizing mitigation efforts for glass surfaces near vegetated areas and/or avoiding use of vegetation near glass.
An array of lake sediment proxies including paleobotanic, geochemical, and historical records has been used to determine former environments of Bugbee Pond, a small, mesotrophic pond in northeastern ...Minnesota. Much research has been produced on the history of climate and vegetation change of the region, yet we have little information on the impact of human settlement. This well-dated, high resolution, multi-proxy record is important for its length and concentration on the historic period. The lake itself became established by ~7000 years ago. Pollen evidence suggests a transition between the regional Prairie Period to the Great Lakes mixed conifer – hardwood forest was established in the region at this time. XRF data suggest dry basin accumulation early in the record after ~7000 cal yr BP, but lake levels substantially increased by ~5600 cal yr BP, during a regionwide climatic transition to more humid conditions. Birch and boreal conifers increased after about 3800 cal yr BP; further increases in boreal conifers occurred by ~2000 cal yr BP. Anthropogenic vegetation changes during the Historic period, beginning in the late 19th century, is well represented by forest clearance of white pine (Pinus strobus), followed by increases in early successional species and an increased sediment accumulation rate due to land clearance. Establishment of farming communities locally are shown by occurrence of corn (Zea mays) and oat (Avena sativa) pollen, and pasturing and grazing are documented by Rumex, Fabaceae and Poaceae pollen, as well as coprophilous fungi, such as Sordaria. The increase and subsequent decline in Pb and S concentrations in the uppermost sediments are mirrored by historically documented, nearby industrial activities.
Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymatic activity until protein resynthesis can occur, along ...with the potential for increased selectivity by targeting uniquely positioned nucleophilic residues in the protein. However, covalent approaches carry additional risk for toxicities or hypersensitivity reactions that can result from covalent modification of unintended targets. Here we describe methods for measuring the reactivity of covalent reactive groups (CRGs) with a biologically relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles. We also describe a computational method for predicting electrophilic reactivity, which taken together can be applied to the prospective design of thiol-reactive covalent inhibitors.
The peptide ligand apelin and its receptor APJ constitute a signaling pathway with numerous effects on the cardiovascular system, including cardiovascular development in model organisms such as ...xenopus and zebrafish.
This study aimed to characterize the embryonic lethal phenotype of the Apj-/- mice and to define the involved downstream signaling targets.
We report the first characterization of the embryonic lethality of the Apj-/- mice. More than half of the expected Apj-/- embryos died in utero because of cardiovascular developmental defects. Those succumbing to early embryonic death had markedly deformed vasculature of the yolk sac and the embryo, as well as poorly looped hearts with aberrantly formed right ventricles and defective atrioventricular cushion formation. Apj-/- embryos surviving to later stages demonstrated incomplete vascular maturation because of a deficiency of vascular smooth muscle cells and impaired myocardial trabeculation and ventricular wall development. The molecular mechanism implicates a novel, noncanonical signaling pathway downstream of apelin-APJ involving Gα13, which induces histone deacetylase (HDAC) 4 and HDAC5 phosphorylation and cytoplasmic translocation, resulting in activation of myocyte enhancer factor 2. Apj-/- mice have greater endocardial Hdac4 and Hdac5 nuclear localization and reduced expression of the myocyte enhancer factor 2 (MEF2) transcriptional target Krüppel-like factor 2. We identify a number of commonly shared transcriptional targets among apelin-APJ, Gα13, and MEF2 in endothelial cells, which are significantly decreased in the Apj-/- embryos and endothelial cells.
Our results demonstrate a novel role for apelin-APJ signaling as a potent regulator of endothelial MEF2 function in the developing cardiovascular system.
Nanette K. Wenger, MD ACCF/AHA Task Force Members Jeffrey L. Anderson, MD, FACC, FAHA, Chair; Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair; Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect; ...Nancy M. Albert, PhD, CCNS, CCRN; Mark A. Creager, MD, FACC, FAHA; David DeMets, PhD; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC; Judith S. Hochman, MD, FACC, FAHA; Frederick G. Kushner, MD, FACC, FAHA; E. Magnus Ohman, MD, FACC; William Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA Table of Contents Developed in Collaboration With the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine Preamble (UPDATED)...e182 Introduction (UPDATED)...e184 Organization of Committee and Evidence Review (UPDATED)...e184 Document Review and Approval (UPDATED)...e185 Purpose of These Guidelines...e185 Overview of the Acute Coronary Syndromes...e186 Definition of Terms...e186 Pathogenesis of UA/NSTEMI...e186 Presentations of UA and NSTEMI...e189 Management Before UA/NSTEMI and Onset of UA/NSTEMI...e189 Identification of Patients at Risk of UA/NSTEMI...e189 Interventions to Reduce Risk of UA/NSTEMI...e190 Onset of UA/NSTEMI...e191 Recognition of Symptoms by Patient...e191 Silent and Unrecognized Events...e191 Initial Evaluation and Management...e191 Clinical Assessment...e191 Emergency Department or Outpatient Facility Presentation...e195 Questions to Be Addressed at the Initial Evaluation...e196 Early Risk Stratification...e196 Estimation of the Level of Risk...e198 Rationale for Risk Stratification...e198 History...e198 Anginal Symptoms and Anginal Equivalents...e198 Demographics and History in Diagnosis and Risk Stratification...e199 Estimation of Early Risk at Presentation...e200 Electrocardiogram...e202 Physical Examination...e203 Noncardiac Causes of Symptoms and Secondary Causes of Myocardial Ischemia...e204 Cardiac Biomarkers of Necrosis and the Redefinition of AMI...e204 Creatine Kinase-MB...e205 Cardiac Troponins...e205 Clinical Use...e205 Clinical Use of Marker Change Scores...e207 Bedside Testing for Cardiac Markers...e208 Myoglobin and CK-MB Subforms Compared With Troponins...e208 Summary Comparison of Biomarkers of Necrosis: Singly and in Combination...e208 Other Markers and Multimarker Approaches...e208 Ischemia...e208 Coagulation ...e209 Platelets...e209 Inflammation...e209 B-Type Natriuretic Peptides...e210 Immediate Management...e210 Chest Pain Units...e211 Discharge From ED or Chest Pain Unit...e212 Early Hospital Care...e213 Anti-Ischemic and Analgesic Therapy...e214 General Care...e215 Use of Anti-Ischemic Therapies...e215 Nitrates...e215 Morphine Sulfate...e217 Beta-Adrenergic Blockers...e217 Calcium Channel Blockers...e219 Inhibitors of the Renin-Angiotensin-Aldosterone System...e220 Other Anti-Ischemic Therapies...e221 Intra-Aortic Balloon Pump Counterpulsation...e221 Analgesic Therapy...e221 Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite (UPDATED)...e221 Antiplatelet Therapy: Recommendations (UPDATED)...e221 Anticoagulant Therapy: Recommendations...e223 Additional Management Considerations for Antiplatelet and Anticoagulant Therapy: Recommendations (UPDATED)...e223 Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite (NEW SECTION)...e224 Newer P2Y12 Receptor Inhibitors...e224 Choice of P2Y12 Receptor Inhibitors for PCI in UA/NSTEMI...e227 Timing of Discontinuation of P2Y12 Receptor Inhibitor Therapy for Surgical Procedures...e227 Interindividual Variability in Responsiveness to Clopidogrel...e228 Optimal Loading and Maintenance Dosages of Clopidogrel...e228 Proton Pump Inhibitors and Dual Antiplatelet Therapy for ACS...e229 Glycoprotein IIb/IIIa Receptor Antagonists (Updated to Incorporate Newer Trials and Evidence)...e230 Older Antiplatelet Agents and Trials (Aspirin, Ticlopidine, Clopidogrel)...e231 Aspirin...e231 Adenosine Diphosphate Receptor Antagonists and Other Antiplatelet Agents...e233 Anticoagulant Agents and Trials...e236 Unfractionated Heparin...e237 Low-Molecular-Weight Heparin...e238 LMWH Versus UFH...e238 Extended Therapy with LMWHs...e241 Direct Thrombin Inhibitors...e241 Factor Xa Inhibitors...e244 Long-Term Anticoagulation...e245 Platelet GP IIb/IIIa Receptor Antagonists...e246 Fibrinolysis...e251 Initial Conservative Versus Initial Invasive Strategies (UPDATED)...e251 General Principles...e252 Rationale for the Initial Conservative Strategy...e252 Rationale for the Invasive Strategy...e253 Timing of Invasive Therapy (NEW SECTION)...e253 Immediate Angiography...e254 Deferred Angiography...e254 Comparison of Early Invasive and Initial Conservative Strategies...e254 Subgroups...e257 Care Objectives...e258 Risk Stratification Before Discharge...e260 Care Objectives...e260 Noninvasive Test Selection...e262 Selection for Coronary Angiography...e263 Patient Counseling...e263 Coronary Revascularization...e263 Recommendations for Revascularization With PCI and CABG in Patients With UA/NSTEMI (UPDATED)...e263 Late Hospital Care, Hospital Discharge, and Post-Hospital Discharge Care...e263 Medical Regimen and Use of Medications...e263 Long-Term Medical Therapy and Secondary Prevention...e265 Convalescent and Long-Term Antiplatelet Therapy (UPDATED)...e266 Beta Blockers...e266 Inhibition of the Renin-Angiotensin-Aldosterone System...e267 Nitroglycerin...e267 Calcium Channel Blockers...e267 Warfarin Therapy (UPDATED)...e267 Lipid Management...e268 Blood Pressure Control...e270 Diabetes Mellitus...e270 Smoking Cessation...e270 Weight Management...e271 Physical Activity...e271 Patient Education...e272 Influenza...e272 Depression...e272 Nonsteroidal Anti-Inflammatory Drugs...e272 Hormone Therapy...e272 Antioxidant Vitamins and Folic Acid...e273 Postdischarge Follow-Up...e273 Cardiac Rehabilitation...e274 Return to Work and Disability...e275 Other Activities...e276 Patient Records and Other Information Systems...e277 Special Groups...e277 Women...e277 Profile of UA/NSTEMI in Women...e278 Management...e278 Pharmacological Therapy...e278 Coronary Artery Revascularization...e278 Initial Invasive Versus Initial Conservative Strategy...e279 Stress Testing...e281 Conclusions...e281 Diabetes Mellitus (UPDATED)...e281 Profile and Initial Management of Diabetic and Hyperglycemic Patients With UA/NSTEMI...e281 Intensive Glucose Control (NEW SECTION)...e282 Coronary Revascularization...e283 Conclusions...e284 Post-CABG Patients...e284 Pathological Findings...e285 Clinical Findings and Approach...e285 Conclusions...e285 Older Adults...e285 Pharmacological Management...e286 Functional Studies...e286 Percutaneous Coronary Intervention in Older Patients...e287 Contemporary Revascularization Strategies in Older Patients...e287 Conclusions...e287 Chronic Kidney Disease (UPDATED) ...e288 Angiography in Patients With CKD (NEW SECTION)...e288 Cocaine and Methamphetamine Users...e290 Coronary Artery Spasm With Cocaine Use...e290 Treatment...e291 Methamphetamine Use and UA/NSTEMI...e292 Variant (Prinzmetal's) Angina...e292 Clinical Picture...e292 Pathogenesis...e292 Diagnosis...e293 Treatment...e293 Prognosis...e293 Cardiovascular "Syndrome X"...e294 Definition and Clinical Picture...e294 Treatment...e295 Takotsubo Cardiomyopathy...e295 Conclusions and Future Directions...e295 Recommendations for Quality of Care and Outcomes for UA/NSTEMI (NEW SECTION)...e297 Quality Care and Outcomes (NEW SECTION)...e297 References...e297 Appendix 1.
The influence of host diversity on multi-host pathogen transmission and persistence can be confounded by the large number of species and biological interactions that can characterize many ...transmission systems. For vector-borne pathogens, the composition of host communities has been hypothesized to affect transmission; however, the specific characteristics of host communities that affect transmission remain largely unknown. We tested the hypothesis that vector host use and force of infection (i.e., the summed number of infectious mosquitoes resulting from feeding upon each vertebrate host within a community of hosts), and not simply host diversity or richness, determine local infection rates of West Nile virus (WNV) in mosquito vectors. In suburban Chicago, Illinois, USA, we estimated community force of infection for West Nile virus using data on Culex pipiens mosquito host selection and WNV vertebrate reservoir competence for each host species in multiple residential and semi-natural study sites. We found host community force of infection interacted with avian diversity to influence WNV infection in Culex mosquitoes across the study area. Two avian species, the American robin (Turdus migratorius) and the house sparrow (Passer domesticus), produced 95.8% of the infectious Cx. pipiens mosquitoes and showed a significant positive association with WNV infection in Culex spp. mosquitoes. Therefore, indices of community structure, such as species diversity or richness, may not be reliable indicators of transmission risk at fine spatial scales in vector-borne disease systems. Rather, robust assessment of local transmission risk should incorporate heterogeneity in vector host feeding and variation in vertebrate reservoir competence at the spatial scale of vector-host interaction.
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