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Plasma fibronectin (pFn) has long been suspected to be involved in hemostasis; however, direct evidence has been lacking. Here, we demonstrated that pFn is vital to control bleeding in fibrinogen-deficient mice and in WT mice given anticoagulants. At the site of vessel injury, pFn was rapidly deposited and initiated hemostasis, even before platelet accumulation, which is considered the first wave of hemostasis. This pFn deposition was independent of fibrinogen, von Willebrand factor, β3 integrin, and platelets. Confocal and scanning electron microscopy revealed pFn integration into fibrin, which increased fibrin fiber diameter and enhanced the mechanical strength of clots, as determined by thromboelastography. Interestingly, pFn promoted platelet aggregation when linked with fibrin but inhibited this process when fibrin was absent. Therefore, pFn may gradually switch from supporting hemostasis to inhibiting thrombosis and vessel occlusion following the fibrin gradient that decreases farther from the injured endothelium. Our data indicate that pFn is a supportive factor in hemostasis, which is vital under both genetic and therapeutic conditions of coagulation deficiency. By interacting with fibrin and platelet β3 integrin, pFn plays a self-limiting regulatory role in thrombosis, suggesting pFn transfusion may be a potential therapy for bleeding disorders, particularly in association with anticoagulant therapy.

Background The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1) antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C-terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP1 42 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites. Methods Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP1 42 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 μg doses of MSP1 42 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 μg dose with a rabies vaccine comparator. Results In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naïve and malaria-experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele) previously tested at both study sites. Conclusions Given that the primary effector mechanism for blood stage vaccine targets is humoral, the antibody responses demonstrated to this vaccine candidate, both quantitative (total antibody titres) and qualitative (functional antibodies inhibiting parasite growth) warrant further consideration of its application in endemic settings. Trial registrations Clinical Trials NCT00666380

Hurricane- and coastal-storm-related losses have increased substantially during the past century, largely due to increases in population and development in the most susceptible coastal areas. Climate change poses additional threats to coastal communities from sea level rise and possible increases in strength of the largest hurricanes. Several large cities in the United States have extensive assets at risk to coastal storms, along with countless smaller cities and developed areas. The devastation from Superstorm Sandy has heightened the nation's awareness of these vulnerabilities. What can we do to better prepare for and respond to the increasing risks of loss? Reducing Coastal Risk on the East and Gulf Coasts reviews the coastal risk-reduction strategies and levels of protection that have been used along the United States East and Gulf Coasts to reduce the impacts of coastal flooding associated with storm surges. This report evaluates their effectiveness in terms of economic return, protection of life safety, and minimization of environmental effects. According to this report, the vast majority of the funding for coastal risk-related issues is provided only after a disaster occurs. This report calls for the development of a national vision for coastal risk management that includes a long-term view, regional solutions, and recognition of the full array of economic, social, environmental, and life-safety benefits that come from risk reduction efforts. To support this vision, Reducing Coastal Risk states that a national coastal risk assessment is needed to identify those areas with the greatest risks that are high priorities for risk reduction efforts. The report discusses the implications of expanding the extent and levels of coastal storm surge protection in terms of operation and maintenance costs and the availability of resources. Reducing Coastal Risk recommends that benefit-cost analysis, constrained by acceptable risk criteria and other important environmental and social factors, be used as a framework for evaluating national investments in coastal risk reduction. The recommendations of this report will assist engineers, planners and policy makers at national, regional, state, and local levels to move from a nation that is primarily reactive to coastal disasters to one that invests wisely in coastal risk reduction and builds resilience among coastal communities.

Hurricane- and coastal-storm-related losses have increased substantially during the past century, largely due to increases in population and development in the most susceptible coastal areas. Climate change poses additional threats to coastal communities from sea level rise and possible increases in strength of the largest hurricanes. Several large cities in the United States have extensive assets at risk to coastal storms, along with countless smaller cities and developed areas. The devastation from Superstorm Sandy has heightened the nation's awareness of these vulnerabilities. What can we do to better prepare for and respond to the increasing risks of loss? Reducing Coastal Risk on the East and Gulf Coasts reviews the coastal risk-reduction strategies and levels of protection that have been used along the United States East and Gulf Coasts to reduce the impacts of coastal flooding associated with storm surges. This report evaluates their effectiveness in terms of economic return, protection of life safety, and minimization of environmental effects. According to this report, the vast majority of the funding for coastal risk-related issues is provided only after a disaster occurs. This report calls for the development of a national vision for coastal risk management that includes a long-term view, regional solutions, and recognition of the full array of economic, social, environmental, and life-safety benefits that come from risk reduction efforts. To support this vision, Reducing Coastal Risk states that a national coastal risk assessment is needed to identify those areas with the greatest risks that are high priorities for risk reduction efforts. The report discusses the implications of expanding the extent and levels of coastal storm surge protection in terms of operation and maintenance costs and the availability of resources. Reducing Coastal Risk recommends that benefit-cost analysis, constrained by acceptable risk criteria and other important environmental and social factors, be used as a framework for evaluating national investments in coastal risk reduction. The recommendations of this report will assist engineers, planners and policy makers at national, regional, state, and local levels to move from a nation that is primarily reactive to coastal disasters to one that invests wisely in coastal risk reduction and builds resilience among coastal communities.

Hurricane- and coastal-storm-related losses have increased substantially during the past century, largely due to increases in population and development in the most susceptible coastal areas. Climate change poses additional threats to coastal communities from sea level rise and possible increases in strength of the largest hurricanes. Several large cities in the United States have extensive assets at risk to coastal storms, along with countless smaller cities and developed areas. The devastation from Superstorm Sandy has heightened the nation's awareness of these vulnerabilities. What can we do to better prepare for and respond to the increasing risks of loss? Reducing Coastal Risk on the East and Gulf Coasts reviews the coastal risk-reduction strategies and levels of protection that have been used along the United States East and Gulf Coasts to reduce the impacts of coastal flooding associated with storm surges. This report evaluates their effectiveness in terms of economic return, protection of life safety, and minimization of environmental effects. According to this report, the vast majority of the funding for coastal risk-related issues is provided only after a disaster occurs. This report calls for the development of a national vision for coastal risk management that includes a long-term view, regional solutions, and recognition of the full array of economic, social, environmental, and life-safety benefits that come from risk reduction efforts. To support this vision, Reducing Coastal Risk states that a national coastal risk assessment is needed to identify those areas with the greatest risks that are high priorities for risk reduction efforts. The report discusses the implications of expanding the extent and levels of coastal storm surge protection in terms of operation and maintenance costs and the availability of resources. Reducing Coastal Risk recommends that benefit-cost analysis, constrained by acceptable risk criteria and other important environmental and social factors, be used as a framework for evaluating national investments in coastal risk reduction. The recommendations of this report will assist engineers, planners and policy makers at national, regional, state, and local levels to move from a nation that is primarily reactive to coastal disasters to one that invests wisely in coastal risk reduction and builds resilience among coastal communities.

Hurricane- and coastal-storm-related losses have increased substantially during the past century, largely due to increases in population and development in the most susceptible coastal areas. Climate change poses additional threats to coastal communities from sea level rise and possible increases in strength of the largest hurricanes. Several large cities in the United States have extensive assets at risk to coastal storms, along with countless smaller cities and developed areas. The devastation from Superstorm Sandy has heightened the nation's awareness of these vulnerabilities. What can we do to better prepare for and respond to the increasing risks of loss? Reducing Coastal Risk on the East and Gulf Coasts reviews the coastal risk-reduction strategies and levels of protection that have been used along the United States East and Gulf Coasts to reduce the impacts of coastal flooding associated with storm surges. This report evaluates their effectiveness in terms of economic return, protection of life safety, and minimization of environmental effects. According to this report, the vast majority of the funding for coastal risk-related issues is provided only after a disaster occurs. This report calls for the development of a national vision for coastal risk management that includes a long-term view, regional solutions, and recognition of the full array of economic, social, environmental, and life-safety benefits that come from risk reduction efforts. To support this vision, Reducing Coastal Risk states that a national coastal risk assessment is needed to identify those areas with the greatest risks that are high priorities for risk reduction efforts. The report discusses the implications of expanding the extent and levels of coastal storm surge protection in terms of operation and maintenance costs and the availability of resources. Reducing Coastal Risk recommends that benefit-cost analysis, constrained by acceptable risk criteria and other important environmental and social factors, be used as a framework for evaluating national investments in coastal risk reduction. The recommendations of this report will assist engineers, planners and policy makers at national, regional, state, and local levels to move from a nation that is primarily reactive to coastal disasters to one that invests wisely in coastal risk reduction and builds resilience among coastal communities.