Interdependencies among SoS elements.
\r\n\tThis publication will aim to collect those projects and research that seek to make buildings, including urban environments, self-sufficient in terms of energy, focusing here on the solutions for HVAC and the energy systems they require and doing so from a double point of view:
\r\n\t- Complexity. As is the case with the automobile and aeronautics industries, buildings have become human-inhabited spaces with an ever-increasing technological load, which will presumably also be used in other ways, as the pandemic associated with COVID-19 has shown. In these scenarios, will HVAC systems be considered as before, or will new solutions have to be considered for new challenges?
\r\n\t- Disruptive technologies. In the coming years, the implementation of technologies such as hydrogen fuel cells, polygeneration of energy, the use of second-use electric batteries in buildings to accumulate energy from renewable energies, or the resolution of constructive solutions with 3D printing will become widespread in buildings. In this scenario, what will be the answers given by those responsible for HVAC systems?
\r\n\tIn addition, concepts such as artificial intelligence, technology transfer, biomimicry, or stigmergy will undoubtedly provide high-value solutions to new and refurbished buildings that society demands.
Urban systems are increasingly under strain as about 54% of the world’s populations currently are city inhabitants [1]. A growing trend of population growth and urbanization will increase this proportion to 66% by 2050. In urban systems, infrastructures constitute the physical framework within which our economy and society operate [2]. Disruptions in infrastructure, therefore, pose considerable threats to some of the very pillars of modern life. Infrastructures including energy, food, water, transportation, manufacturing, and telecommunications are key components in enabling modern society to function.
\nFrom a conceptual point of view, urban infrastructure can be considered as a couple human-engineered system. An engineered system (ES) is
Recent structural changes, such as deregulation in the energy sector, have revealed infrastructure’s vulnerabilities. Public dissatisfactions began to surface as the lack of capacity, reliability, and vulnerability of such provisions become increasingly prevalent causing politicians to take serious considerations. At the same time, many infrastructures have appeared to be inert to change because these infrastructures have long technical life time and are deeply interwoven in our social, economic, and political structure. Lack of systematic knowledge in addressing uncertainties may contribute to ad hoc political decisions, which may block timely adaptation and discourage further investment in the infrastructure system [4].
\nA system-of-systems (SoS) perspective is an attempt to structure the complexity of human-engineered systems by taking a broader view than just the physical design (i.e., traditional system engineering view) and operational aspect, to include commercial and financial, economic, social, and policy aspects couched within multiple levels. The goal is to improve analysis for decision-making.
\nA system-of-systems (SoS) consists of multiple, heterogeneous, distributed systems embedded in networks at multiple levels that evolve over time. Complexity in an SoS stems primarily from the heterogeneity of its constituent systems, the distributed nature of these systems. The complexity brought by the system heterogeneity exists both within a domain (e.g., power generation) and across domains (e.g., power generation, energy service economics, and governmental policy/regulation).
\nThe chapter first describes a generic SoS conceptual model that characterizes the interdependencies among SoS constituents. Next, a model of uncertainty space evolution over time is presented. Three case studies are then presented to illustrate the framework. In the last section, the added values of SoS framework are discussed.
\nAn SoS consists of constituent systems that include individual engineered and actor system (Figure 1). An engineered system (ES) represents the performance and capabilities of relevant physical/technological systems. An actor system (AS) represents the development and operation of resources by an actor and, possibly, the management of other actor behavior residing either horizontally at the same SoS level or vertically across level.
\nSystem-of-systems constituents: (a) engineered system and (b) actor system.
The model is described using system model elements that are central to the policy analysis approach [5]. Policies (P) are the set of instruments within the control of the decision makers that can change the system. External forces (X) refer to factors that are not controllable by the decision maker but may influence the system significantly. The structure of an actor system can be specified as a set of endogenous factors (I) together with relationships (R), which may include functional, behavioral, or causal ones. The results of these interactions, the model outputs, are called outcomes of interest (O). The value systems (W) of decision makers and stakeholders reflect their goals and preferences. Notice that an engineered system is devoid of policy instruments and has no value systems.
\nAn SoS of urban systems can then be constructed via assemblage of some ES and AS systems in a structure resembling the nested system in Figure 2. Each element represents an ES, which resides at the lowest level (α level) and an AS, which resides at the β level and above.
\nA system-of-systems consisting of engineered (ES) and actor systems (AS).
Based on the framework, several terms can be defined:
A scenario is a single realization of one set of external forces (X).
System structure is the configuration of E and R.
Uncertainty space,
The different types of interdependencies within an SoS are given in Table 1. The system model variables in an SoS interact with one another, creating a network of interrelationships. These interdependencies are bidirectional. In one direction, the interdependency can manifest in a form of influence.
\nLinkage of interdependencies | \nFormalism | \n
---|---|
An outcome of an ES is an external factor for another ES | \n\n\n | \n
An outcome of an ES is an external factor for an AS | \n\n\n | \n
An outcome of an ES influences actor decision | \n\n\n | \n
An actor’s decision is an external factor for an ES | \n\n\n | \n
An actor’s decision is an external factor for another actor | \n\n\n | \n
An actor’s decision influences another actor’s decision | \n\n\n | \n
The realization of an outcome of interest of an actor affects the decision of another actor | \n\n\n | \n
A value system of one actor becomes an exogenous factor of another | \n\n\n | \n
The outcomes of one actor system affect the value system of another actor | \n\n\n | \n
Interdependencies among SoS elements.
To deal with uncertainties in a system-of-systems, a computational approach called exploratory modeling and analysis (EMA) has been proposed [6, 7]. EMA is founded on the idea of exploring multiple hypotheses about the SoS of interest by varying the assumptions underlying the system model. EMA is used to explore the implications of multiple hypotheses about the system by means of computational experiments. A computational experiment is a single computer run of the system model using one set of assumptions.
\nFigure 3 shows an ‘uncertainty space funnel’ that models how the future realizations of the model variables will unfold in a time horizon of
The evolution of SoS uncertainty space.
Uncertainty spaces at one particular period can be modeled in different ways. For example, the
Three main characteristics of SoS uncertainty space are described as follows:
The degree and scope of uncertainty increases as the time period progresses. This is a default characteristics since the longer the time span the greater the uncertainty.
The degree and scope of uncertainty actually decreases as time progresses. This occurs, for example, in case the threshold market share of a certain technology is reached, which reduces the range of the share of other technologies (i.e.,
The nature of the uncertainty space in one period is different from that in the subsequent period, which may also depend on the realization preceding it. For example, when a structural change (I, R) occurs, some of the variables become irrelevant and new ones need to be added. Also, the value system of decision makers and stakeholders may change over time. Future decision makers may have different decision criteria or put different weights on the criteria.
This way of characterizing SoS uncertainty space highlights its path dependency nature. Suppose that
An urban system is a complex system comprising an infrastructure-actor network, whose complexity is confounded by their close physical proximity and functional interdependencies. An understanding of its complexities can support policymakers to maintain quality of life amidst perturbations, growth and decay, discontinuities, and stress in the system. Building upon [8], we aim to establish the level of influence and vulnerability of a network of multiple infrastructure-actor networks in urban systems.
\nAn overall urban system comprises several individual systems such as energy, water, telecommunication, and transportation. We develop a typology for classifying different types of system interdependency (Figure 4), which is based on (1) whether the network accounts for the connectivity within an individual system (i.e., intrasystem) or across systems (i.e., intersystem) and (2) whether the context of such connectivity takes place in an emergency condition (i.e., with drastic service discontinuities) or in a non-emergency one.
\nA typology of urban system complexities.
To a certain extent, each of the resulting quadrants has a different focus of inquiry and hence policy implications in terms of actors’ actions and coordination. For instance, the first quadrant (Q1) focuses on connectivity within a single sector (e.g., transportation) in a non-emergency condition. An example of inquiry in this sector may revolve around the issue of reducing traffic congestion. By contrast, in the third quadrant (Q3), the inquiry considers interdependencies among multiple sectors (e.g., a city as a whole) and addresses broader issues (e.g., impacts of extreme weather events). In this chapter, we focus on the fourth quadrant.
\nNetwork theory is employed to obtain measures that can illuminate the degree of infrastructure influence and vulnerability within an urban system. We consider a particular infrastructure as a node. A directional link between two nodes means that the failure in the source affects the end node. This formulation implies that fewer links among nodes are actually desirable. We use and interpret sample data from [9] to model the (inter)dependencies among infrastructure and the repair team for the urban systems in Florida during the 2004 hurricane season. The resulting network model of infrastructure-actor connectivity is depicted in Figure 5. To generate some network measures, we employ the UCINET software [10].
\nInfrastructure-actor network in the context of Florida urban systems.
A summary of the network measures is given in Table 2. Each of the measures and its implication is described later.
\nSummary results of network analysis of urban infrastructure systems.
It counts the number of outgoing (i.e., influence) and incoming (i.e., dependence) links. For the case study, road infrastructure exerts the most influence to others, whereas (waste) water plant and electricity transmission receive most influence from others and hence are most vulnerable. This insight can inform prioritizing infrastructures that need to be decoupled from other.
\nThis measures node importance in terms of its role as an ‘intermediary’ in a failure path. The electricity plan appears to play the most dominant role. Consequently, urban system needs to be disconnected with electricity plant by, for example, having own backup power.
\nIt measures the importance of an infrastructure not only by the number of nodes it affects but also the importance of the nodes to which it affects. It appears that the supervisory control and data acquisition (SCADA) system is the infrastructure with the highest score because it affects three very important nodes such as electricity transmission, electricity plant, and phone/Internet infrastructure.
\nOur initial work employs network theory to establish the degree and influence and vulnerability of infrastructure-actor interdependency in urban systems. The insight obtained from the work can potentially be used to set priority of actions and to find a balance between vulnerability and performance.
\nUncertainties abound in making investment decisions in energy infrastructure such as electricity power plant. There are some major uncertainties they have to deal with in liberalized energy markets ([11]). It is difficult to predict the future electricity demand price as well as the price of input fuels. In addition, there are several structural uncertainties. These include regulation on price mechanisms (e.g., price cap) and environment (e.g., cooling water, emissions, and waste), the developments in the natural gas industry (e.g., the extraction of gas through fracking), and the unbundling of the energy industry into separate electricity generation, transmission, and distribution function.
\nAn SoS model for electricity power plant investment is given in Figure 6. It consists of two engineered (power plant and house building technologies) and three actor systems (utility companies, household consumers, and public utilities commission).
\nSoS model for electricity power plant investment.
Some of the main elements of system-of-systems model are described as follows:
Policies (P): At the beta level, policy variables for utility companies involved: the size of the plant, the timing of plant construction, and maintenance policies. These are the actions that would become external forces to the power plant technologies at the alpha level. For the household consumers, their decisions are mainly associated with energy consumption and investments in energy saving measures, which in turn affect house building technologies (at alpha level).
External forces (X): At the beta level, the utility companies would be concerned and uncertain factors such as electricity pricing regulations, macroeconomic variables, and technological options. The household consumers would be uncertain about natural gas price, electricity demand, and electricity price. At the gamma level, the public utilities seemingly would face uncertainties about political climate and dynamics in societal values.
Endogenous factors I: For utility companies, they are the variables that determine the cash flow of the investment: (1) installed and used capacity, (2) costs: construction (sunk cost), fixed and variable operations costs, and fuel, and (3) revenues.
Outcome of interest (O): Profitability is one key outcome for utility companies, which will be measured in net present value (NPV). For public utilities commissions, one outcome they want to monitor is the level of service reliability and affordability.
The relationships (R): For utility companies, the relationships involved include: (1) revenue functions, (2) cost functions, and (3) functions that translate the costs, revenues, and discount factors (i.e., interest rate) into NPV.
The value system of the decision makers (W): Utility companies are driven to maximize profitability. In contrast, the utilities commissions are mandated to promote and protect public interests.
Based on the abovementioned definition of SoS, a simple computational model of electricity infrastructure investment was developed. In response to these uncertainties, utility companies may choose not to invest in capital intensive, long lead-time generating technologies such as large nuclear- or hydropower plants or in technologies with relatively high pollution such as coal plant. Instead, they may opt for cheaper, smaller, and less polluting plants that have shorter lead times to build [12].
\nThe model compares the performance of two alternative investment decisions.
The uncertainty space for the investment decisions spans a period of 20 years and is discretized into an interval of 10 years. Major uncertainties of future conditions over the time span include several factors. First is electricity demand of which an annual growth rate range between −5 and 5% was taken. Second is the change in electricity price that was assumed to grow between −20 and 20% per 10 year. Lastly, the volatility of natural gas price is modeled using a binomial method [13]. The gas price change follows a ‘random walk’ pattern with specific upward (up) and downward (down) movement factor.
\nTo assess the success of investment decisions, three decision criteria are used: net present value (NPV), regret, and robustness criterion. A regret value represents the difference between the NPV of a decision compared to the NPV of the
A robustness score represents the ratio of the number of successful scenarios with the total number of scenarios. Four categories of robustness can be specified. The robustness falls into Category I if the score is between 1 and 0.75 and Category II for the score between 0.5 and 0.74. A decision is considered robust if it has Category I and II score. Decision makers should then compare the robustness of decision alternatives and choose a decision with maximum robustness.
\nComputational experiments were performed across the uncertainty space. The resulting regret category and robustness score of
Investment robustness outcomes (a) Investment1 (563 MW) and (b) Investment2 (264 MW).
In a multiple period decision problem, the robustness score can be further aggregated by taking score average. In this way, the path dependency of decision performance can be traced back to the time when the decision is made (i.e., Period0). The nested robustness score for
Decision makers are also interested in knowing other conditions that will make their seemingly promising decision fail. To illustrate sensitivity, analysis was performed on the interest rate, which has been held constant at 5%. Figure 8 shows that the ranges of interest rate that will make Investment1 fail. For example, when the interest rate reaches 11%, the Investment1 is no longer robust across some of the most favorable conditions in period1 because all the robustness scores fall into Categories III and IV.
\nSensitivity of favorable scenarios to interest rate.
The economy of the Northern Illinois Region, USA with Rockford as its largest city has suffered since the late 1980s as a result of the decline of manufacturing industry. Currently, a diverse initiative has been launched by various agencies to try to reverse the trend.
\nThe case study presents a development of a decision-support tool to inform policymakers and stakeholders to revive the region’s economy. To this end, the proposal will implement a holistic system approach. The approach used will be a combined system dynamics and SOS perspective. The issues that will be addressed include the interactions between the city quality of life factors and investment decisions.
\nThe combined SOS perspective and system dynamics have a capability to model economic decisions at three different levels such as city, company, and individual. Figure 9 shows the multi-level decision making occurring within a macroeconomic context.
\nSoS for urban systems.
System dynamics is an approach to understand the behavior of complex systems over time. It deals with internal feedback loops and time delays that affect the behavior of the entire system. It employs a causal loop and a stock and flow model to represent the change and accumulation of system variables (Figure 10a, b, respectively).
\nSystem dynamics main building blocks (a) causal loop and feedback diagram. (b) Stock and flow diagram.
At the macroeconomic level, the approach captures the relationships between key economic factors of production (labor, land, capital, and technology) and economic output (e.g., production and GDP) (Figure 11).
\nA macroeconomic view of urban system interdependencies.
At this level, several causal and feedback loops can be identified. We can identify, for example, two loops associated with migration. An increase in net migration will add to work force, and availability of work force will in turn reduce the rate of net migration (Loop 1). In the same way, an increase in migration will increase the competition for housing (reduced house availability) and availability of housing will make the city more attractive (increased net migration) (Loop 2).
\nFor the greater Rockford area, for instance, much efforts have been put in to increase the attractiveness for companies to invest (Source). The efforts focus on industrial infrastructure but also on factors contributing to the quality of life (school quality, housing, safety, health care, recreation facilities and parks) (Figure 12). They clearly want exploit the positive feedback in which companies expect quality workers, who in turn is attracted by improved quality of life.
\nInterrelationships between investment decisions and city attractiveness.
At company level, an issue of interest is how investment decisions affect the production capacity and company’s hiring (Figure 13).
\nCompany’s hiring mechanism as a response to customer orders.
The level of regional employment (at macroeconomic level) depends on the number of job vacancies at companies. The demand for workers will be driven by the need to fill production capacity, which in turn depends on customers’ orders as they are influenced by how well the economy is doing (i.e., economic growth at macroeconomic level).
\nAt individual motivational level, research has suggested psychological behavior that can be best captured using system dynamics [14]. Figure 14 illustrates factors that are affecting workers’ motivation at work and their accomplishments. For instance, quality of work will depend on the effort devoted, which in turn depends on work pressure.
\nWorker’s motivation and work accomplishment dynamics.
Urban systems are facing pressures from population growth, urbanization, and climate change. Keeping the status quo could lead to failures in the systems. Given these challenges, better understanding of various elements of urban systems and their interdependencies is needed to inform decisions to improve the systems.
\nThe chapter presents a system-of-systems (SoS) framework to structure complexity of urban systems. A way to deal with future uncertainties within urban system SoS is described. As a whole, SoS forms a network of decision makers and engineered systems at various levels. Over time, the elements of SoS and their relationships will evolve. Their uncertainties can be handled using a computational approach called exploratory modeling and analysis (EMA).
\nThe framework described in the chapter is applied to three case studies. Each case study highlights a unique aspect of urban systems. Different tools were employed to generate insights relevant for decision-making. The first case study looked at the vulnerabilities of urban system under perturbations and disruptions. It uses data related to urban infrastructure in Florida, USA that was devastated by hurricane. Network theory was applied to identify nodes of infrastructure that are influential in causing system failures and are critical for recovery.
\nThe second case study assesses the performance of alternative investment decisions on electricity power plant. EMA is applied to define and explore uncertainty space in terms of measures of regret and robustness of each investment alternative. Once a preliminary robust decision has been identified, EMA can reveal a set of circumstances that may cause the decision to fail. The last case study conceptualizes the dynamics of urban economic revival within a larger macroeconomic environment. A system dynamics tool was employed to represent the context of an economic region in Midwest, USA. Detailed causal loop and stock-and-flow models were developed to specify factors and their relationships across individual, company, and city level.
\nPulmonary embolism (PE) is a type of venous thromboembolism (VTE) that is potentially fatal but can be treated with different types of therapy. PE is an obstruction of the pulmonary arteries that can be caused by a clot, tumor, fat, or air. PE occurs when a portion of a blood clot breaks off and travels until it lodges in the pulmonary arteries [1]. Most deep vein thrombosis will develop in the lower extremities, but up to half can lead to PE [2]. PE is a significant health issue in the US, since there is an increased prevalence of this condition in the elderly. Other risk factors include obesity, heart failure, and cancer [3].
Current anticoagulation management guidelines prefer direct oral anticoagulants (DOAC) such as dabigatran, rivaroxaban, apixaban, and edoxaban for initial and long-term therapy for treating PE [4]. DOACs are preferred over vitamin K antagonist (VKA) therapy. This is due to the similar risk reduction for recurrent VTE, reduced risk of bleeding, and improved patient and provider convenience over the intensive monitoring associated with VKA therapy [4]. Each of the DOACs has demonstrated similar efficacy outcomes compared to VKA therapy with recurrent embolism [4]. In contrast, the risk of bleeding differs with the DOACs, which demonstrate less risk when compared to warfarin [4]. One possible exception to this, however, is that gastrointestinal bleeding may be higher with dabigatran, rivaroxaban, and edoxaban compared to warfarin. This has been observed in patients treated with atrial fibrillation [4]. Treatment recommendations differ when managing PE in special populations such as cancer, pregnancy, obesity, elderly, renal dysfunction, hepatic dysfunction, and COVID-19. Low-molecular-weight heparin (LMWH) is recommended over VKA therapy in cancer-associated thrombosis. Evidence suggests that LMWH is more effective in reducing recurrent embolism in this population and is more reliable in patients who have difficulty tolerating oral intake. It further removed the need for frequent monitoring of the international normalized ratio (INR) [4]. The prevention of PE in hospitalized patients includes either LMWH, low-dose unfractionated heparin (UFH) administered twice or three times daily, or fondaparinux [5]. Bleeding remains a concern with anticoagulation therapy. With the availability of reversal agents, clinicians have been able to push the boundaries of PE management with confidence in both the inpatient and outpatient settings.
The duration of anticoagulant therapy for PE is 3 months, at minimum, which may be extended or indefinite in selected circumstances [4]. In patients with a PE provoked by surgery or a nonsurgical transient risk factor, the recommended duration of anticoagulation is 3 months [4]. In patients with an unprovoked PE, bleeding risk determines the duration, but in patients with high bleeding risk, the duration remains at 3 months. In low to moderate bleeding risk, the duration of therapy becomes indefinite [4].
UFH is a parenteral anticoagulant that works by inactivating thrombin (IIa) and factor Xa
The IV route is the preferred mode of administration in shock and/or hypotension due to the absorption variability from subcutaneous tissues secondary to UFH plasma protein binding [6]. Dosing and special considerations for UFH are discussed in Table 1.
Drug | Dose | Special considerations |
---|---|---|
UFH 1 | 80 unit/kg IV bolus, followed by an 18-unit/kg/h infusion [6]. | |
Enoxaparin | 1 mg/kg subQ 2 BID 3 [13, 14]. | |
Dalteparin | 200 IU/kg/day 4 subQ for one month, followed by 150 IU/kg/day subcutaneously for months 2 through 6 [15]. | Maximum of 18,000 IU per day. |
Fondaparinux | <50 kg:5 mg subQ daily 50–100 mg: 7.5 mg subQ daily >100 kg: 10 mg subQ daily | Initiate warfarin within 72 h and give concomitantly for at least 5 days. |
Edoxaban | 60 mg po once daily; 30 mg once daily if body weight ≤ 60 kg | Not for use in patients with CrCl >95 mL/min 5. Dose after 5 to 10 days of initial therapy with a parenteral anticoagulant. |
Apixaban | 10 mg po twice daily for 7 days followed by 5 mg twice daily [16]. | |
Rivaroxaban | 15 mg po twice daily x 3 weeks, then 20 mg once daily x at least 6 months [17]. | Take with food to improve absorption [18, 19, 20] |
Dabigatran | 150 mg po BID [34].; 110 mg BID for patients ≥80 years | Dose after 5 to 10 days of initial therapy with a parenteral anticoagulant. Reduce dose to 110 mg BID for patients ≥80 years or ≥ 75 years with at least one bleeding risk factor. |
Anticoagulant dosing and special considerations.
UFH: unfractionated heparin.
subQ: subcutaneously.
BID: twice a day.
IU: international units.
CrCL: creatinine clearance.
Some adverse drug reactions of concern are thrombocytopenia and major bleeding, such as intracranial and gastrointestinal bleeds. Heparin-associated thrombocytopenia can present in two forms. There is an early, benign, reversible nonimmune thrombocytopenia form and a late, more serious immunoglobulin G (IgG)-mediated immune thrombocytopenia type, referred to as heparin-induced thrombocytopenia (HIT). HIT poses a concern with UFH use in the treatment of PE, with the overall incidence being reported to be up to 7% in patients with a mortality of 20–30% and varies depending on factors such as patient population (surgical vs. medicine), duration of heparin use, and the type of heparin administered [8, 9]. UFH has a threefold higher risk of HIT compared to LMWH and serious limb-threatening and life-threatening complications [10]. The mechanism of HIT stems from IgG formation against the heparin/PF4 complex on platelets. Once IgG binds to the heparin/PF4 complex on platelets, the platelets become activated, resulting in venous and arterial thrombi formation [10, 11]. Monitoring platelets every 2–4 days or more frequently in higher-risk patients is recommended in patients on treatment doses of heparin [11]. Another side effect of concern is the significant reduction in bone density reported in about 30% of adult patients and the symptomatic bone fractures that occur in 2–3% of adult patients receiving heparin for at least 1 month or more [12].
A complete outline of first line and alternate reversal agents utilized for anticoagulants for PE management is outlined in Table 2. Protamine sulfate is a reversal agent indicated for the reversal of UFH- and LMWH-associated bleeds. This agent is administered by a slow IV infusion at doses <5 mg/min due to the concerns of anaphylaxis, hypotension, bradycardia, and respiratory toxicity associated with the rapid infusion [13]. Due to UFH’s short half-life, a reversal agent may not be necessary for most cases, as the UFH effect will normalize due to its rapid clearance [13].
First-line reversal agent | Alternative reversal agents | |
---|---|---|
UFH 1 | Protamine sulfate | |
LMWH 2 | Protamine sulfate | |
VKA 3 | 4F-PCC 4 | FFP 5 |
Dabigatran | Idarucizumab | PCC 6 |
aPCC 7 | ||
Direct oral factor-Xa inhibitors | Andexanet alfa | PCC |
aPCC | ||
Fondaparinux | Factor VIIa | aPCC |
Andexanet alfa |
Recommended reversal agents for anticoagulant therapy.
UFH: Unfractionated heparin.
LMWH: low molecular weight heparin.
VKA: vitamin K antagonist.
4F-PCC: 4-factor prothrombin complex concentrate.
FFP: fresh-frozen plasma.
PCC: prothrombin complex concentrate.
aPCC: activated prothrombin complex concentrate.
LMWHs, including enoxaparin and dalteparin, are defined as having a mean molecular weight that is less than 50% of that of UFH. They offer the advantage of consistent anticoagulant effect administered subcutaneously and dosing by body weight. Dosing and special considerations for LMWH (enoxaparin and dalteparin) are discussed in Table 1. LMWH is currently the preferred anticoagulant for active malignancy and pregnancy. However, newer study findings support the notion that DOACs may benefit VTE treatment in cancer patients [14].
Thrombocytopenia and major bleeding are also possible adverse effects of concern. While the risk of HIT is lower with LMWH in comparison with UFH, a baseline platelet count is suggested as a basis from which to contemplate the development of HIT. Further treatment with LMWH should be avoided in patients with a known history of HIT. Although it less likely to trigger the formation of HIT antibodies than UFH, LMWHs are just as effective as UFH in triggering platelet activation by HIT antibodies [12].
Routine anti-Xa monitoring is generally not recommended for enoxaparin but can be considered in patients with severe or unstable renal function and obese patients with a BMI ≥ 40 kg/m2 (or > 190 kg) who will be on enoxaparin for longer than 1 to 2 weeks [13, 14]. The anti-Xa level peak is drawn 4 h after the enoxaparin dose is administered when a steady state is achieved with a target range of 0.6–1.0 IU/mL [14, 21]. Monitoring anti-Xa activity in morbidly obese patients >120–140 kg and patients with severe or unstable renal function may be considered for dalteparin with a target anti-Xa range of 0.5–1.5 IU/mL [15]. Similar to enoxaparin, the anti-Xa levels in patients taking dalteparin must be drawn 4–6 h after the dalteparin dose is administered and once a steady state is achieved (receiving at least 3 to 4 doses) [15].
LMWHs are only partially reversed by protamine (60 to 80%), since binding only occurs with long, large-molecular-weight heparin proteins [13]. Due to its small size, fondaparinux is not reversed by protamine [13]. Protamine is known to interact with platelets, fibrinogen, and other plasma proteins. This may result in an anticoagulant effect of its own; thus, the minimal amount of protamine required to neutralize heparin present in the plasma should be administered [13].
VKA such as warfarin is a vitamin K receptor antagonist that continues to play a role in PE treatment, particularly in patients with severe renal insufficiency, antiphospholipid syndrome, and financial constraints who are unable to afford DOACs [22]. International normalized ratio (INR) monitoring is recommended for warfarin monitoring [23]. Due to the drug’s long half-life, slow depletion of factor II, and rapid depletion of anticoagulant protein C, patients are bridged with UFH, LMWH, or fondaparinux for at least 5 days and until the INR reaches the therapeutic range of 2 to 3. [24].
Frequent monitoring may be a barrier to initiating this agent. Furthermore, several food and drug interactions may also limit the desire to initiate warfarin for long-term therapy. Food that is high in vitamin K content such as oils, fats, liver, nuts, and green vegetables may decrease the efficacy of warfarin. Medications that are inducers and inhibitors of CYP2C9, 2C19, 1A2, and 3A4 must require dose adjustments and/or more frequent monitoring of their INR. For these reasons, patients are educated about maintaining consistency with their vitamin K intake and encouraged to discuss any dietary or medication changes with their healthcare provider [25].
Vitamin K is recommended for warfarin reversal if the INR is >10 without significant bleeding and with repeated vitamin K doses every 6–24 h as needed [55]. Vitamin K can be administered by IV or the oral route, with a preference for oral administration; there is an associated risk of anaphylactoid reactions in 3 out of 10,000 patients when IV formulations were administered [56]. Subcutaneous injection is not recommended due to a delayed and unpredictable effect [55]. The availability of 4F-PCC (KCentra®) during the last decade has resulted in its use over FFP as a reversal agent for warfarin-associated bleeding complications. This agent has been employed especially for life-threatening bleeding, where 4F-PCC has demonstrated 25 times more potency in replacing vitamin K-dependent clotting factors than FFP [53]. The limitations of FFP in comparison with 4F-PCC include its slower onset, risks of allergic reaction and infection transmission, blood group compatibility, longer preparation time, and higher volume [53]. A major advantage of 4F-PCCs is their ability to be stored at room temperature as a lyophilized powder and the fact that they can quickly be reconstituted and administered [53]. With life-threatening bleeding, the addition of vitamin K 5 to 10 mg by slow IV infusion is suggested [57].
Fondaparinux (Arixtra®) is a synthetic pentasaccharide anticoagulant selectively inhibiting factor Xa
The most common adverse reaction associated with the use of fondaparinux is bleeding complications. While most other agents used for PE management do have a reversal agent, this medication does not. Fondaparinux does not require laboratory monitoring. However, periodic complete blood count, serum creatinine level, stool occult tests, and anti-Xa level can be monitored on an individual basis [26].
For fondaparinux, recombinant activated factor VII and aPCC have some data in human and animal studies, respectively, as reversal agents. Both andexanet alfa (a recombinant factor Xa) and aripazine have been shown to bind to Xa inhibitors but lack any human data with fondaparinux [54].
Apixaban is an oral direct factor Xa inhibitor approved for the treatment and prevention of DVT and PE [16]. Dosing and special considerations for apixaban use for PE treatment are discussed in Table 1. The oral bioavailability is approximately 50%, with most of the drug absorption occurring in the small intestine [29]. Drug elimination occurring
Andexanet alfa (Andexxa®) can be used to reverse apixaban (off-label) in life-threatening or uncontrollable bleeding. The dosing is based on the specific factor Xa agent-inhibitor to be reversed, dose, and the time since the last dose was administered [58]. Andexanet alfa 400 mg intravenous bolus is administered at a rate of 30 mg/min, followed by 4 mg/min
Rivaroxaban is an oral direct factor Xa inhibitor approved for the prevention and treatment of DVT and PE. Dosing and special considerations for rivaroxaban use for PE treatment are discussed in Table 1. The oral bioavailability ranges from approximately 80 to 100% for a 10 mg dose and up to 66% for a 20 mg [31, 32, 33]. Bioavailability of doses ≥15 mg is improved with food [31, 32, 33]. Renal elimination accounts for approximately 36% of unchanged drug, its use in patients with a CrCL <30 mL/min is not advised, and <15 mL/min employment is contraindicated [31, 32, 33]. Rivaroxaban is not dialyzable [31, 32, 33]. Rivaroxaban follows a similar elimination pattern to that of apixaban, with metabolism through the CYP3A4 systems accounting for 57% elimination [31, 32, 33]. P-glycoprotein system inhibitors may lead to elevated rivaroxaban serum levels [28, 29, 30]. Rivaroxaban’s terminal half-life ranges between 5 and 9 h, with a prolonged half-life of 11–13 h seen in elderly patients [31, 32, 33]. The steady-state concentrations for this agent tend to occur within 3 days. The premature discontinuation of any anticoagulant, including rivaroxaban, increases the risk of thrombotic events and is listed as a black box warning [17]. To minimize this risk, an alternate coverage should be considered, should rivaroxaban be discontinued for a reason apart from pathological bleeding or therapy completion [17]. Epidural or spinal hematomas have been observed in patients managed with rivaroxaban undergoing neuraxial anesthesia or spinal puncture. Such hematomas are known to result in long-term or permanent paralysis [17].
Andexanet alfa (Andexxa®) can also be used to reverse rivaroxaban (off-label) in life-threatening or uncontrollable bleeding. Rivaroxaban doses of greater than 10 mg, or if an unknown amount is administered within 8 h or at an unknown time, are managed with the high-dose andexanet alfa regimen [58].
Dabigatran (Pradaxa®) is a direct thrombin (IIa) inhibitor approved for the prevention and treatment of DVT and PE. Dosing and special considerations for dabigatran use for PE treatment are discussed in Table 1. Dabigatran should be initiated 0–2 h before the next dose of parenteral anticoagulant would have been due, or at the time of discontinuation of UFH continuous infusion [34]. The medication has low oral bioavailability and undergoes hepatic metabolism. P-glycoprotein (P-gp) inducers, such as phenobarbital, rifampin, and fosphenytoin, reduce exposure to dabigatran and should be avoided [34]. In contrast, P-glycoprotein (P-gp) inhibitors increase exposure to dabigatran, and recommendations vary based on the P-gp inhibitor and the indication for dabigatran use [34]. Renal impairment and P-gp inhibition are the major independent risk factors for increased dabigatran exposure and increased risk of bleeding. Hence, renal function assessment at baseline and periodically thereafter is recommended. Dose adjustments for dabigatran doses in patients with severe renal impairment (CrCl 30 mL/min or less) are recommended. Caution must be used in the elderly, as the risk of stroke and bleeding increases with age, as seen in an analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial [35]. Dabigatran is contraindicated for use in patients with mechanical heart valves. The RE-ALIGN (Randomized, Phase II Study to Evaluate the sAfety and Pharmacokinetics of oraL dabIGatran Etexilate in Patients after Heart Valve replacement) trial was terminated early due to thromboembolic events (valve thrombosis, stroke, and myocardial infarction), and major bleeding was observed in the dabigatran group compared to the warfarin group in heart valve patients [36].
Besides major and minor bleeding, gastrointestinal adverse effects have been reported in studies at an incidence rate ranging from 24.7 to 35% [34]. The gastrointestinal adverse effects reported include but are not limited to dyspepsia, gastritis, abdominal pain or discomfort, and epigastric discomfort [34]. Due to the prevalence of these adverse effects, it is necessary to educate the patient about the potential side effects and advise them not to abruptly discontinue the medication before notifying their healthcare provider [34].
One distinguishing feature of dabigatran is the increase in bioavailability by 75% that occurs if the capsule is broken, chewed, or emptied out of the capsule shell [34]. This leads to an increased risk of toxicity, such as major bleeds [34]. Since the capsule cannot be manipulated due to the stated reason, the medication should not be administered
There is a specific reversal agent approved for dabigatran. The agent named idarucizumab (Praxbind®) is a monoclonal antibody with 350 times more affinity for dabigatran than thrombin [15, 51]. Diuresis may also help with the excretion of dabigatran as well [34].
Edoxaban is an oral direct factor-X inhibitor approved in the United States for the treatment of PE. Approval was based primarily on the Hokusai VTE study, which evaluated 3319 patients with PE. The trial showed that edoxaban was not inferior to warfarin but had a lower bleeding risk [37]. Dosing and special considerations for edoxaban use for PE treatment are discussed in Table 1. The oral bioavailability is approximately 60%, and renal elimination accounts for approximately 50% of unchanged drug. Edoxaban’s terminal half-life ranges between 10 and 14 h. Interestingly, edoxaban blood levels are lower in patients with better renal function averaging about 40% less in patients with CrCL >95 mL/min when compared to those with CrCl >50 to ≤80 mL/min [38]. Bleeding complications such as hemorrhage (major or minor) appear to be the most common adverse effects associated with edoxaban use [38, 39]. Lastly, andexanet alfa (Andexxa®) can also be used to reverse edoxaban (off-label) in life-threatening or uncontrollable bleeding [58].
Thrombolytic therapy for PE may be administered systemically or directed by a catheter into the pulmonary arteries to accelerate the resolution of acute PE. Thrombolytic therapy can lower pulmonary artery pressure and increase arterial oxygenation [22]. Studies limiting thrombotic therapy in acute PE have shown the best outcomes by restricting it to patients presenting with a massive (high-risk) PE [22, 59]. Patients presenting with hemodynamic instability, right ventricular dysfunction, and without significant risk of bleeding are considered potential candidates for emergency thrombolytic therapy [4, 60]. The results from timely administration of thrombolytic therapy may be seen within 36 h [61]. Mortality rates occur in up to 30% of patients categorized as high risk and make the timing of therapeutic intervention critical [62, 63, 64]. Adverse events, especially the high incidence of bleeding and hemorrhagic stroke, require careful consideration prior to starting thrombolytic therapy [65, 66]. Systemic alteplase (Activase®) is the only FDA-approved thrombolytic for the management of acute massive (high risk) hemodynamically unstable PE [67]. All anticoagulants must be stopped prior to the initiation of alteplase and 100 mg IV infused over 2 h is the most common regimen. Alternative weight-based regimens for patients weighing <65 kg may be considered [68]. A weight-based regimen with a 15 mg bolus followed by 0.75 mg/kg over 30 min (max 50 mg) and then 0.5 mg/kg over the next 30 min (max 35 mg) have shown efficacy without increased bleeding [68]. Intra-catheter-directed alteplase 0.5–2 mg/h for 2–15 h for a total dose of 4–24 mg has been used successfully in facilities by experienced physicians and well-designed protocols, but this route of administration is not FDA approved [69]. Tenecteplase (TNKase®) and reteplase (Retavase®) have been used for acute massive (high risk) PE, but are not FDA approved for use in patients with PE [70, 71].
Therapeutic anticoagulation is the gold standard for the management of VTE. The narrow therapeutic efficacy window creates challenges in drug selection and monitoring to deliver the appropriate dose to prevent further embolic events while not causing a life-threatening bleed. Historically, guidelines in VTE management include the option of continuous UFH; however, LMWH and direct factor Xa inhibitors have begun to displace UFH as first-line agents [1, 5, 34]. Traditionally, aPTT has served as the marker of therapeutic anticoagulation in patients with VTE due to the exclusive use of UFH [40, 41, 42, 43, 44, 45, 46, 47]. Despite decades of experience with aPTT values, challenges in the precision monitoring of anticoagulation continue to create therapeutic dilemmas for clinicians [41, 42]. The lack of standardized methods in monitoring and individualized patient factors, including biological variables and heparin resistance, are credited as most problematic when using aPTT to measure the effect of UFH [43, 44]. While aPTT values remain the standard for measuring the effects of UFH, anti-factor Xa (anti-Xa) heparin assay (HA) is recommended as a monitoring option in place of aPTT values by the American College of Chest Physicians (ACCP) and the College of American Pathologists (CAP) [34, 39]. Anti-Xa levels demonstrate greater consistency in measuring anticoagulation, since they are based on the functional activity of all heparins [46, 47]. Comparatively, the aPTT test measures the function of the intrinsic and common pathways of the coagulation cascade, which can have significant variability among individuals [38, 42, 43].
The implementation of heparin dosing protocols has improved the uniformity of therapeutic anticoagulation with UFH. Most of these protocols are “weight-based,” and changes in the units of UFH per hour are adjusted based on the aPTT values [50]. This method of dosing UFH has led to concerns regarding both “over” and “under” anticoagulation using aPTT-level directed therapy. Combining aPTT and anti-Xa levels has been proposed as a method to overcome the variable swings commonly seen in patients with multiple comorbidities, obesity, older age (>70 years), 16 drug-induced coagulopathies, pharmacokinetic changes, and preexisting genetic alterations [37, 38, 40, 42, 45, 46, 47]. Some hospital systems have transitioned from the use of aPTT to anti-Xa HA altogether and are reporting the faster attainment of therapeutic anticoagulation in addition to the elimination of multiple laboratory tests and dosage changes [46].
Based on numerous studies, anti-Xa levels have been shown to be a viable alternative to aPTT to achieve and maintain therapeutic anticoagulant levels with UFH [36, 40, 43, 48, 49, 50]. Anti-Xa levels have provided a more consistent method of monitoring a patient’s response to UFH and demonstrate fewer blood samples and dosage adjustments compared to aPTT values [42, 47].
INR monitoring is recommended more frequently upon warfarin initiation (once a day) and can be extended to typically once a month once INR is stable and in a therapeutic range [25].
Routine laboratory monitoring is not indicated for DOAC, but anti-factor Xa (FXa) can be useful for excluding clinically important levels of DOAC [53]. Edoxaban may elevate the PT and aPTT, but FXa activity may be a better measure of effectiveness [39]. Fondaparinux does not require laboratory monitoring as well. Anti-factor Xa activity is probably the assay for monitoring fondaparinux but is not usually obtained in real time [54]. For the qualitative assessment of dabigatran, thrombin time (TT) and aPTT may be used, with TT being sensitive to dabigatran even at low drug concentrations [53].
Anticoagulant dosing of obese patients with PE remains to be an area that has not been well studied [72]. The bulk of the data comes from pharmacokinetic/pharmacodynamic (PK/PD) studies and subgroup analyses of premarketing trials comparing obese patients to patients with normal body weight [52, 53, 54, 72]. Furthermore, warfarin appears to have the most robust data available in this population. Warfarin pharmacokinetics have been compared in various studies of obese patients with a BMI > 30 and 40 kg/m2 to normal body weight subjects. These studies found that obesity was associated with a greater delay and dosage to achieve a therapeutic INR. Data associated with the risk of bleeding, however, have been conflicting, indicating that obesity may or may not increase the risk [72]. While warfarin has the most robust data in this population, the usage of warfarin appears to be on the decline [72].
Dabigatran is a direct thrombin inhibitor that sets it apart from other DOACs. Subgroup analyses of Phase 3 trials for VTE (RE-LY) and atrial fibrillation (RECOVER) suggested no significant differences in the efficacy and safety outcomes of obese patients in comparison with those with lower body weights [53, 54]. In contrast, treatment failures have been documented in morbidly obese patients using standard doses. The authors reported that standard doses failed to achieve “therapeutic levels,” suggesting a higher volume of distribution (Vd) and a higher clearance [55, 56].
The factor X inhibitors, rivaroxaban, apixaban, and edoxaban also have some data in obese populations. Rivaroxaban was evaluated in a small PK/PD study involving a heterogeneous group of subjects including those in the obese range (>120 kg). The half-life, Vd, and clearance declined slightly with increasing body weight. The authors felt the declines were not clinically relevant [57]. A separate PK/PD analysis using pooled data from the phase ll EINSTEIN DVT and ODIXa-DVT trials reported similar findings. These studies enrolled some patients with BMIs >35 kg/m2 and found clinical benefits comparable across all weight groups [58]. The authors of this analysis also concluded that standard doses should be sufficient to treat obese patients; however, a review questioned whether the data were robust enough to draw that conclusion [52, 58].
In the apixaban’s phase 1 PK/PD study, the pharmacokinetic data were somewhat different compared to those for rivaroxaban. The overall Vd was higher in subjects >120 kg or BMI > 30 kg/m2 than normal body weight subjects. The half-life declined almost proportionately to the increase in Vd (27% ↓ vs. 24% ↑ for half-life and Vd, respectively). Peak level and area under the plasma drug concentration-time curve (AUC) were also reduced in the higher body weight subjects. The authors concluded the differences were unlikely to be of clinical significance [59]. The phase 3 trials, ARISTOTLE and AMPLIFY, contained a significant proportion of patients with body weights >100 kg and BMIs above 30 kg/m2. Subgroup analyses found no differences in efficacy; however, more bleeding episodes were reported in the ARISTOTLE trial. Whether the increase in hemorrhagic complications between these trials was due to age, renal clearance, or other patient-specific factors is unclear [60, 61, 62].
Edoxaban has less data than other DOACs. Phase 3 Hokusai-VTE enrolled a large group of patients >100 kg. There was no difference in efficacy and safety compared to groups with other weights [63].
A recent international retrospective study of LMWHs examined dosing in obesity regarding capped (<18,000 IU/d) and uncapped dosages (>18,000 IU/d). The data were obtained from the RIETE Registry, a large prospective case series of patients with VTE. LMWHs included enoxaparin, dalteparin, and tinzaparin. The authors reported that the results may be subject to selection bias despite attempts to control for potential confounders in multivariable analysis. Nevertheless, they found that after adjustment for multiple potential confounders, patients with obesity (>100 kg or BMI >30 kg/m2) who received capped doses were at a lower risk of having the composite outcome of VTE recurrences, major bleeding, or all-cause death at 15 and 90 days. Bleeding was also reduced with capped dosages [64].
A recent retrospective study of UFH for acute venous thromboembolism (VTE) compared three body mass index (BMI) cohorts: (i) non-obese (less than 30 kg/m2), (ii) obese (30 to 39.9 kg/m2), and (iii) morbid obesity (⩾40 kg/m2). The dosing employed was based on actual body weight. The median times to therapeutic aPTT were reported as 16.4, 16.6, and 17.1 h in each of the three cohorts [65].
Obese patients on warfarin may require a higher dose or more time to achieve a therapeutic INR. Bleeding risk may or may not be greater. Available data for DOACs other than dabigatran suggested usual doses may not negatively impact efficacy in obese patients. Apixaban studies reported conflicting results on bleeding risk. However, there are probably insufficient data for DOACs to suggest that usual doses would be adequate in the subgroup of morbidly obese patients. Obese patients with capped doses of LMWHs may have better efficacy and safety outcomes. Capped dosages are conditionally recommended in the 2018 American Society of Hematology guidelines [66].
Anticoagulants have been evaluated in CKD and ESKD patients in various PK/PD and clinical efficacy trials [67]. The PK/PD of warfarin in CKD and ESKD is not completely understood [67, 68]. Official dosing guidelines do not recommend an alteration of dose [67]. Warfarin is extensively metabolized by the cytochrome P450 type 2C9 (CYP2C9) enzyme [84]. Although not removed by dialysis, there are no data evaluating whether this procedure alters its pharmacokinetics and pharmacodynamics [67]. One study comparing individuals with a GFR of 30–59 mL/min and healthy controls reported a shorter half-life and increased clearance. Other data showed that CKD, especially GFRs <30 mL/min per 1.73 m2 or ESKD, complicates warfarin therapy [70, 71]. These data reported that lower doses were required to maintain therapeutic INR with greater fluctuations in INR values and higher risks of major bleeding events for any given INR value. A recent meta-analysis of ESKD patients with atrial fibrillation found that warfarin had no benefit in reducing ischemic stroke incidence. The authors concluded that the drug appeared to be associated with a significantly higher risk of hemorrhagic stroke but no increased risk of other types of major bleeding. They also found no change in mortality [72, 73]. How all these data apply to other indications such as PE is unknown.
The various DOACS have also been evaluated in renal disease. A small study of dabigatran using reduced doses (150 mg daily for CKD and 50 mg daily for ESKD) examined the effect of CKD and ESKD on pharmacokinetic parameters. Subjects with a creatinine clearance <30 mL/min demonstrated a 6.5-time increase in the AUC with a doubling of the half-life compared to normal controls [74].
Rivaroxaban has somewhat conflicting data in CKD and ESKD. In a phase 3 trial subgroup analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), the authors reported that reduced renal function (creatinine clearances <80 mL/min) had no impact on rivaroxaban’s effectiveness and safety [75]. In contrast, a PK/PD study comparing dialysis patients to normal controls reported a 56% increase in AUC when 15 mg doses were administered after dialysis [90]. The AUC was decreased by only 5% when administered pre-dialysis suggesting dialysis is ineffective in clearing the drug [90]. Another PK/PD study comparing three ranges of renal insufficiency to normal controls reported AUCs of 1.4-, 1.5-, and 1.6-fold higher in cases of creatinine clearance concentrations of 50–80, 30–50, and < 30 mL/min, respectively [76].
Pharmacokinetic data for apixaban appear similar to those of rivaroxaban, except that the incremental upsurges in AUC are somewhat lower in magnitude. A small PK/PD study using a 5 mg dose in ESKD patients and normal controls found a 36% increase in AUC in the ESKD group compared to controls. The apixaban dose was administered pre-dialysis [77]. Another small PK/PD study used a single 10 mg dose and compared subjects with varying degrees of CKD to normal controls [13]. Compare to the controls, the AUCs increased by 16%, 29%, and 38% in the CKD cohorts with creatinine clearances of 50–80, 30–50, and < 30 mL/min, respectively. The mean half-life was only slightly increased in the total CKD population (17 h) compared to the controls (15 h) [77]. The overall results for both studies were not unexpected, as apixaban is metabolized more extensively and demonstrates less unchanged renal elimination than other DOACs [1]. Again, the drug appears to be poorly dialyzable [67].
Edoxaban was evaluated in a small PK/PD study comparing CKD subjects to normal controls. The data, available as an abstract only, showed that the mean AUCs increased by 32%, 74%, and 72% with creatinine clearances of 50–80, 30–50, and < 30 mL/min (not on dialysis), respectively [67]. The mean AUC for subjects on peritoneal dialysis was 93% [67]. Similar to other Factor Xa inhibitors, edoxaban is poorly cleared by hemodialysis [78].
Probably, the best data for LMWH come from a subgroup analysis of the ExTRACT TIMI 25 trial. This study compared a 1 mg/kg per day dose of enoxaparin to UFH in ST-elevation myocardial infarction (STEMI) patients with CrCLs less than 30 mL. There was no significant difference in mortality or recurrent MI (33 vs. 37.7%) and in bleeding risk (5.7 vs. 2.8%) for enoxaparin and UFH, respectively. Mortality increased for both drugs as renal function declined [94].
UFH is rapidly eliminated by the reticular endothelial system and, to a lesser extent, the kidney. However, the degree to which the RES functions in this role varies from person to person. Nevertheless, lower doses in VTE treatment are recommended to reduce bleeding risk. An advantage for UFH over enoxaparin is the ability to reverse the former easier with protamine [16, 79].
All DOACs increase AUC with the magnitude inversely proportional to renal function. These drugs may be the anticoagulants of choice for stages 1, 2, and 3 CKD [95]. Some sources recommend apixaban as an alternative to warfarin in selected patients with ESKD [67]. Warfarin, although predominately metabolized in the liver, may require a lower dose to reach a therapeutic INR. Historically, it is the oral anticoagulant of choice in ESKD [16, 79]. However, how does warfarin’s potential lack of benefit in ESKD patients with AF apply to PE? Are LMWHs better than UFH? Both were associated with similar mortality increases in STEMI patients with declining kidney function. Should these data also apply to renal failure patients and PE?
Patients with cirrhosis typically have elevated INR and aPTT. As a result, there have been misconceptions that these patients are “autoanticoagulated.” However, patients with liver disease may have a substantially increased risk of VTE (RR 1.74 (95% CI, 1.54–1.95) for liver cirrhosis and 1.87 (95% CI, 1.73–2.03) for non-cirrhotic liver disease) [95]. A meta-analysis in patients with the liver disease found the incidence of PE from nine studies to be 0.28% (95% CI 0.13–0.49%) and the prevalence of PE from two studies to be 0.36% (95% CI 0.13–0.7%) [96].
Determining the ideal anticoagulant to use after a PE in a patient with liver cirrhosis may be challenging. Warfarin can be safely used in patients with liver dysfunction. Elevations in baseline INR due to liver disease, however, may lead to unclear INR targets during warfarin therapy [80, 81]. LMWHs have a good safety profile with liver dysfunction; however, subcutaneous administration may limit compliance, and lower anti-Xa levels in liver dysfunction limit efficacy monitoring [82, 83]. Finally, there are a lack of data on using DOACs in patients with liver disease. Clinical trials with DOACs excluded patients with liver disease as most DOACs are predominantly cleared hepatically (apixaban 75%, rivaroxaban 65%, edoxaban 50%, and dabigatran 20%) [84, 85]. Therefore, dosing recommendations are derived from pharmacokinetic studies (Table 3).
Mild impairment (Child-Pugh Class A) | Moderate impairment (Child-Pugh Class B) | Severe impairment (Child-Pugh Class C) | |
---|---|---|---|
Apixaban | No dosage adjustment. | Use with caution. No dosage adjustments provided. | Use is not recommended. |
Rivaroxaban | No dosage adjustment. | Avoid use. | Avoid use. |
Edoxaban | No dosage adjustment. | Use is not recommended. | Use is not recommended. |
Dabigatran | No dosage adjustment. | Use with caution. No dosage adjustments provided. | No dosage adjustments provided. |
FDA recommendations of DOACs in liver dysfunction.
Regardless of which anticoagulant is chosen, the risk of bleeding should be thoroughly evaluated. In patients with liver disease, bleeding can be due to varices, portal hypertensive gastropathy, peptic ulcer disease, and arteriovenous malformations. A small, 45-patient cohort study, comparing DOACs to warfarin/LMWH found no difference in thrombotic events. Still, there were significantly fewer major bleeding episodes in the DOAC group (1 patient [4%] vs. 5 patients [28%],
Cancer patients have a five- to sevenfold increased risk for VTE within the first year of diagnosis [101]. Additionally, VTE is considered an independent predictor of mortality in these patients [87, 88]. The pathophysiological and epidemiological association between PE and cancer is well established. For decades, LMWHs were considered a first-line therapy for cancer-associated PEs, as knowledge of the efficacy and safety of DOACs in cancer patients was lacking [89, 90, 91]. Since then, four large randomized control trials have been published comparing DOACs with LMWH that have highlighted the utilization of most DOACs for the treatment of PEs [90, 92, 93, 94].
The Hokusai VTE Cancer trial randomized 1050 cancer patients with acute VTE to either edoxaban, an oral direct factor Xa inhibitor, or dalteparin, an LMWH. The trial found that edoxaban was non-inferior to dalteparin for the primary outcome of recurrent VTE or major bleeding during a follow-up period of 12 months (95% confidence interval 0.70 to 1.36;
SELECT-D randomized 406 patients with cancer and acute VTE to oral rivaroxaban, a factor, or dalteparin for a treatment duration of 6 months [108]. SELECT-D was a 6-month open-label, pilot, randomized control study that compared rivaroxaban 15 mg BID for 3 weeks then 20 mg once daily to dalteparin (200 IU/kg once daily for 1 month, then 150 IU/kg once daily) in patients with VTE and solid or hematologic cancers [108]. The trial found that the VTE recurrence rate was 4% with rivaroxaban and 11% with dalteparin (HR 0.43, 95% CI 0.19 to 0.99) [108]. Major bleeding occurred in 4% with dalteparin and 6% with rivaroxaban (HR 1.83, 95% CI 0.68 to 4.96) and clinically relevant, nonmajor bleeding occurred in 4% with dalteparin and 13% with rivaroxaban (HR 3.76, 95% 1.63 to 8.69) [108].
CARAVAGGIO was an open-label, non-inferior study that randomized 1170 patients to apixaban (10 mg twice daily for 7 days, then 5 mg twice daily) or dalteparin (200 IU/kg once daily for 1 month, then 150 IU/kg once daily) for 6 months of treatment [109]. The trial resulted in a VTE recurrence rate of 5.6% with apixaban and 7.9% with dalteparin (risk difference − 2.3%; HR 0.63, 95% CI 0.37 to 1.07,
Given that these oral agents have shown efficacy and provide a more convenient medication dosage form, we have already begun to see a shift in the way PEs are treated in cancer patients [90, 92, 93, 94]. However, since many of these studies have excluded patients with GI tumors or a history of GI bleeding, it is still recommended to continue using LMWH in these patients due to the higher GI bleeding risk seen with DOACs. [90, 92, 93, 94]. If a DOAC is to be utilized, the choice of which oral anticoagulant to be used in a cancer patient should be made on an individual basis with considerations of drug interactions with chemotherapy agents and the type of cancer.
UFH and LMWH remain the only currently available choices for the safe management of VTE including PE during pregnancy and puerperium. UFH provides the least exposure to the fetus and risk to the mother, since it does not cross the placenta, is not distributed into breast milk, and the dose is easily titrated [110]. LMWHs have a similar safety profile as UFH for the fetus since they also do not cross the placenta. Concerns about distribution into breast milk have been raised [110, 111]. Most studies have not demonstrated that the LMWH levels in breast milk are high enough to cause coagulopathy when using standard prophylaxis doses. Further studies are needed for a complete safety profile.
The ability to easily monitor aPPT levels for UFH and anti-Xa levels for LMWHs provides clinicians with the ability to maintain therapeutic concentrations throughout pregnancy. Therapeutic-level monitoring provides safety and efficacy for both the fetus and the mother, since changes in the drug volume of distribution and clearance progressively increase throughout pregnancy [22, 110, 112, 113, 114]. Additionally, UFH and LMWH have short half-lives, allowing for anticoagulation to be maintained within 24 h of delivery and permitting the safe use of neuroaxial anesthesia if needed [111, 115]. Restarting LMWH within 6 h postdelivery in patients without bleeding concerns has been shown to be safe. Anticoagulation should be maintained during puerperium [110]. Thromboprophylaxis for future pregnancies with UFH or LMWH is recommended for women at risk [116, 117].
The safety profile and pharmacokinetics of DOACs currently do not favor their use during pregnancy or puerperium, since they cross the placenta and distribute into breast milk [110, 118]. The use of DOACs may be considered in women who are not or are no longer breastfeeding. The inability to readily monitor DOAC levels limits the clinician’s ability to maintain therapeutic levels throughout pregnancy and puerperium due to the pharmacokinetic changes listed above. Maintaining a safe and therapeutic efficacious anticoagulation regimen up to and through the time of delivery requires a multidisciplinary effort and needs to be closely coordinated [110, 111, 115].
The risk of thromboembolic disease, including PE, increases with age [119, 120, 121]. The trauma to the vascular endothelium caused by a thromboembolic event places the patient at a higher risk of recurrence, requiring prolonged anticoagulation [119, 122]. Comorbidities accompanying aging, especially cardiovascular and pulmonary disease, add to the complexity of treatment of thromboembolic disease [123]. The increased risk for bleeding further complicates the safe management of an acute venous thromboembolic event, and prolonged anticoagulation is required to prevent future events [4].
PE in elderly patients may not present with the typical symptoms seen in younger patients, making early diagnosis more challenging in this population. Several studies have found syncope to be the most frequent presenting symptom in elderly patients, versus pleuritic chest pain in a younger population [124, 125, 126]. Early pharmacotherapy intervention is critical to prevent further thrombus formation, regardless of the patient’s age [119].
Recommendations for initial treatment for PE in a stable patient regardless of the prognosis include DOACs (apixaban or rivaroxaban) or initial LMWH, followed with dabigatran or edoxaban. LMWH or UFH and warfarin may be preferred in patients with reduced renal function (CrCL <30 mL/min) [127].
Stable patients with a good prognosis may be managed in an outpatient setting. The current recommendations for stable patients with a poor prognosis require hospitalization [127]. A thorough medication history is important prior to starting a DOAC due to the potential drug–drug interactions seen with this class of anticoagulants. P-glycoprotein inhibitors or CYP3A4 inhibitors or inducers should be avoided, since they can alter the plasma of DOACs [127]. The unstable patient requires hospitalization and may be a candidate for thrombolytic therapy, preferably by catheter-directed thrombolysis [127].
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from Wuhan, Hubei province, China, in December 2019 has adversely impacted the world. Among the several complications related to SARS-CoV-2 is VTE [128], a systematic review of 3487 COVID-19 patients from 30 studies demonstrated VTE incidence to be 26%, 12% for PE with or without DVT, and 14% for DVT alone.
The etiology of PE in COVID-19 is secondary to the well-known VTE risk factors, with indirect aspects of the severity of illness and direct effects of SARS-CoV2 viral infection. These patients are at VTE risk due to the recurrent use of intravascular access devices, sedation, and vasopressors, within the intensive care unit (ICU) setting. These factors promote stasis. Respiratory failure, hypoxia, comorbidities, multi-organ failure, obesity, and prolonged immobility are other elements. Additional confounding factors include a history of VTE and or neoplasm, sepsis, surgery, trauma, or stroke [97, 98].
COVID-19 is associated with a profound early response of proinflammatory cytokines. This may result in a cytokine storm, increased risk of vascular hyperpermeability, multi-organ failure, and death [129, 130]. While thrombin’s primary role is to accelerate clot formation
Both LMWH and UFH are recommended for VTE prophylaxis and PE treatment in COVID-19 patients. The recommended dose of the LMWH enoxaparin for VTE prophylaxis is 40 mg (4000 IU) daily. An intermediate dose of LMWH enoxaparin 40 mg subcutaneously every 12 h is recommended in the critically ill, the obese, and those patients with multiple VTE risk factors. A UFH dose of 5000 IU Q8H is recommended for VTE prophylaxis, and doses of up to 7500 IU have been employed in critically ill patients [105, 106, 107, 108, 109]. DOACs are recommended in stable patients and in the post-acute phase of PE and outpatient settings when the benefits from their use outweigh the risks. Renal function monitoring with dosage modifications is recommended when LMWH, UFH, and DOACs are employed. Additionally, Anti-Xa monitoring is recommended in patients requiring the therapeutic anticoagulation with LMWH, UFH, and DOAC therapy. DOAC plasma level monitoring is also recommended [106, 110]. Therapeutic anticoagulation should always be considered first; thrombolytic therapy is recommended in patients who go to develop sub-massive or massive PE. An inferior vena cava filter may be employed in at-risk patients; extracorporeal membrane oxygenator (ECMO) is an option, in conjunction with surgical embolectomy or catheter-directed management [1, 111, 112]. Several weeks of therapy is recommended with LMWH or DOACs, post-hospitalization for COVID-19 patients [132].
PE is a medical emergency that affects thousands of Americans each year. Thousands of Americans die from this condition annually. The therapy for PE has evolved over the years. Traditional therapies such as UFH, VKA, and warfarin are being abandoned by clinicians in favor of LMWH and DOACs. Reversal agents such as 4-factor prothrombin complex concentrate, andaxanet alfa, and the monoclonal antibody idarucizumab have allowed clinicians to push the boundaries of PE management with confidence, particularly in the outpatient setting. Special populations, such as obese, renal dysfunction, liver impairment, cancer, pregnancy, and COVID-19 patients with PE, pose a tremendous therapeutic burden and challenge to clinicians. Despite these challenges, tremendous progress has been made, with demonstrated improved patient outcomes in PE treatment over the last three decades.
The authors declare no conflict of interest.
IntechOpen - where academia and industry create content with global impact
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Over the past few decades, no major new types of antibiotics have been produced and almost all known antibiotics are increasingly losing their activity against pathogenic microorganisms. The levels of multi-drug resistant bacteria have also increased. It is known that worldwide, more than 60% of all antibiotics that are produced find their use in animal production for both therapeutic and non-therapeutic purposes. The use of antimicrobial agents in animal husbandry has been linked to the development and spread of resistant bacteria. Poultry products are among the highest consumed products worldwide but a lot of essential antibiotics are employed during poultry production in several countries; threatening the safety of such products (through antimicrobial residues) and the increased possibility of development and spread of microbial resistance in poultry settings. This chapter documents some of the studies on antibiotic usage in poultry farming; with specific focus on some selected bacterial species, their economic importance to poultry farming and reports of resistances of isolated species from poultry settings (farms and poultry products) to essential antibiotics.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Christian Agyare, Vivian Etsiapa Boamah, Crystal Ngofi Zumbi and\nFrank Boateng Osei",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"261271",title:"MSc.",name:"Crystal Ngofi",middleName:null,surname:"Zumbi",slug:"crystal-ngofi-zumbi",fullName:"Crystal Ngofi Zumbi"},{id:"261272",title:"MSc.",name:"Frank Boateng",middleName:null,surname:"Osei",slug:"frank-boateng-osei",fullName:"Frank Boateng Osei"},{id:"261273",title:"Dr.",name:"Vivian Etsiapa",middleName:null,surname:"Boamah",slug:"vivian-etsiapa-boamah",fullName:"Vivian Etsiapa Boamah"}]},{id:"49246",doi:"10.5772/61300",title:"Chitosan as a Biomaterial — Structure, Properties, and Electrospun Nanofibers",slug:"chitosan-as-a-biomaterial-structure-properties-and-electrospun-nanofibers",totalDownloads:4727,totalCrossrefCites:27,totalDimensionsCites:63,abstract:"Chitosan is a polysaccharide derived from chitin; chitin is the second most abundant polysaccharide in the world, after cellulose. Chitosan is biocompatible, biodegradable and non-toxic, so that it can be usedin medicalapplications such as antimicrobial and wound healing biomaterials. It also used as chelating agent due to its ability to bind with cholesterol, fats, proteins and metal ions.",book:{id:"4648",slug:"concepts-compounds-and-the-alternatives-of-antibacterials",title:"Concepts, Compounds and the Alternatives of Antibacterials",fullTitle:"Concepts, Compounds and the Alternatives of Antibacterials"},signatures:"H. M. Ibrahim and E.M.R. El- Zairy",authors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"},{id:"175694",title:"Dr.",name:"Enas",middleName:null,surname:"El- Zairy",slug:"enas-el-zairy",fullName:"Enas El- Zairy"}]},{id:"70919",doi:"10.5772/intechopen.90891",title:"Antimicrobial Effect of Titanium Dioxide Nanoparticles",slug:"antimicrobial-effect-of-titanium-dioxide-nanoparticles",totalDownloads:1817,totalCrossrefCites:21,totalDimensionsCites:47,abstract:"The widespread use of antibiotics has led to the emergence of multidrug-resistant bacterial strains, and therefore a current concern for food safety and human health. The interest for new antimicrobial substances has been focused toward metal oxide nanoparticles. Specifically, titanium dioxide (TiO2) has been considered as an attractive antimicrobial compound due to its photocatalytic nature and because it is a chemically stable, non-toxic, inexpensive, and Generally Recognized as Safe (GRAS) substance. Several studies have revealed this metal oxide demonstrates excellent antifungal and antibacterial properties against a broad range of both Gram-positive and Gram-negative bacteria. These properties were significantly improved by titanium dioxide nanoparticles (TiO2 NPs) synthesis. In this chapter, latest developments on routes of synthesis of TiO2 NPs and antimicrobial activity of these nanostructures are presented. Furthermore, TiO2 NPs favor the inactivation of microorganisms due to their strong oxidizing power by free radical generation, such as hydroxyl and superoxide anion radicals, showing reductions growth against several microorganisms, such as Escherichia coli and Staphylococcus aureus. 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Aggregation continues with the maturation of biofilm. Dispersion is started by certain conditions such as phenol-soluble modulins (PSMs). By this way, sessile bacteria turn back into planktonic form. Bacteria embedded in biofilm (sessile form) are more resistant to antimicrobials than planktonic bacteria. So it is hard to treat biofilm-embedded bacteria than planktonic forms. For this reason, it is important to detect biofilm. There are a few biofilm detection and biofilm production methods on prosthetics, methods for screening antibacterial effect of agents against biofilm-embedded microorganism and antibiofilm effect of agents against biofilm production and mature biofilm. The aim of this chapter is to overview direct and indirect methods such as microscopy, fluorescent in situ hybridization, and Congo red agar, tube method, microtiter plate assay, checkerboard assay, plate counting, polymerase chain reaction, mass spectrometry, MALDI-TOF, and biological assays used by antibiofilm researches.",book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"63397",doi:"10.5772/intechopen.80624",title:"Antibiotic Resistance in Lactic Acid Bacteria",slug:"antibiotic-resistance-in-lactic-acid-bacteria",totalDownloads:2486,totalCrossrefCites:12,totalDimensionsCites:21,abstract:"Most starter cultures belong to the lactic acid bacteria group (LAB) and recognized as safe by the US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). However, LAB may act as intrinsic or extrinsic reservoirs for antibiotic resistance (AR) genes. This fact may not constitute a safety concern itself, as the resistance gene transfer is vertical. Nevertheless, external genetic elements may induce changes that favor the horizontal transfer transmission of resistance from pathogens as well as from the human intestinal microbiota, which represents a severe safety issue. Some genus of AR LAB includes Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, and Streptococcus isolated from fermented meat and milk products. Currently, the WHO recommends that LAB used in the food industry should be free of resistance. Therefore, the objective of this chapter is to present an overview of the LAB antibiotic resistance and some methods to determine the same.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Yenizey M. 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After attachment, aggregation of bacteria is started by cell-cell adhesion. Aggregation continues with the maturation of biofilm. Dispersion is started by certain conditions such as phenol-soluble modulins (PSMs). By this way, sessile bacteria turn back into planktonic form. Bacteria embedded in biofilm (sessile form) are more resistant to antimicrobials than planktonic bacteria. So it is hard to treat biofilm-embedded bacteria than planktonic forms. For this reason, it is important to detect biofilm. There are a few biofilm detection and biofilm production methods on prosthetics, methods for screening antibacterial effect of agents against biofilm-embedded microorganism and antibiofilm effect of agents against biofilm production and mature biofilm. The aim of this chapter is to overview direct and indirect methods such as microscopy, fluorescent in situ hybridization, and Congo red agar, tube method, microtiter plate assay, checkerboard assay, plate counting, polymerase chain reaction, mass spectrometry, MALDI-TOF, and biological assays used by antibiofilm researches.",book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"62553",title:"Antibiotic Use in Poultry Production and Its Effects on Bacterial Resistance",slug:"antibiotic-use-in-poultry-production-and-its-effects-on-bacterial-resistance",totalDownloads:7339,totalCrossrefCites:43,totalDimensionsCites:92,abstract:"A surge in the development and spread of antibiotic resistance has become a major cause for concern. Over the past few decades, no major new types of antibiotics have been produced and almost all known antibiotics are increasingly losing their activity against pathogenic microorganisms. The levels of multi-drug resistant bacteria have also increased. It is known that worldwide, more than 60% of all antibiotics that are produced find their use in animal production for both therapeutic and non-therapeutic purposes. The use of antimicrobial agents in animal husbandry has been linked to the development and spread of resistant bacteria. Poultry products are among the highest consumed products worldwide but a lot of essential antibiotics are employed during poultry production in several countries; threatening the safety of such products (through antimicrobial residues) and the increased possibility of development and spread of microbial resistance in poultry settings. 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Kocazeybek",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"},{id:"248288",title:"Prof.",name:"Bekir",middleName:null,surname:"Kocazeybek",slug:"bekir-kocazeybek",fullName:"Bekir Kocazeybek"},{id:"406463",title:"Dr.",name:"Nesrin",middleName:null,surname:"Gareayaghi",slug:"nesrin-gareayaghi",fullName:"Nesrin Gareayaghi"}]},{id:"63397",title:"Antibiotic Resistance in Lactic Acid Bacteria",slug:"antibiotic-resistance-in-lactic-acid-bacteria",totalDownloads:2497,totalCrossrefCites:13,totalDimensionsCites:21,abstract:"Most starter cultures belong to the lactic acid bacteria group (LAB) and recognized as safe by the US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). However, LAB may act as intrinsic or extrinsic reservoirs for antibiotic resistance (AR) genes. This fact may not constitute a safety concern itself, as the resistance gene transfer is vertical. Nevertheless, external genetic elements may induce changes that favor the horizontal transfer transmission of resistance from pathogens as well as from the human intestinal microbiota, which represents a severe safety issue. Some genus of AR LAB includes Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, and Streptococcus isolated from fermented meat and milk products. Currently, the WHO recommends that LAB used in the food industry should be free of resistance. Therefore, the objective of this chapter is to present an overview of the LAB antibiotic resistance and some methods to determine the same.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Yenizey M. 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It also used as chelating agent due to its ability to bind with cholesterol, fats, proteins and metal ions.",book:{id:"4648",slug:"concepts-compounds-and-the-alternatives-of-antibacterials",title:"Concepts, Compounds and the Alternatives of Antibacterials",fullTitle:"Concepts, Compounds and the Alternatives of Antibacterials"},signatures:"H. M. Ibrahim and E.M.R. El- Zairy",authors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"},{id:"175694",title:"Dr.",name:"Enas",middleName:null,surname:"El- Zairy",slug:"enas-el-zairy",fullName:"Enas El- Zairy"}]}],onlineFirstChaptersFilter:{topicId:"897",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81704",title:"Quorum Sensing Inhibition Based Drugs to Conquer Antimicrobial Resistance",slug:"quorum-sensing-inhibition-based-drugs-to-conquer-antimicrobial-resistance",totalDownloads:22,totalDimensionsCites:0,doi:"10.5772/intechopen.104125",abstract:"Quorum sensing is the cell to cell communication mechanism in microorganism through signalling molecules. Regulation of virulence factor, sporulation, proteolytic enzymes production, biofilm formation, auto-inducers, cell population density are key physiological process mediated through quorum-sensing (QS) signalling. Elevation of innate immune system and antibiotic tolerance of pathogens is highly increased with perspective of quorum-sensing (QS) activity. Development of novel drugs is highly attractive scenario against cell-cell communication of microbes. Design of synthetic drugs and natural compounds against QS signal molecules is vital combat system to attenuate microbial pathogenicity. Quorum sensing inhibitors (QSIs), quorum quenchers (QQs), efflux pump inhibitors (EPIs) act against multi-drug resistance strains (MDR) and other pathogenic microbes through regulation of auto-inducers and signal molecule with perceptive to growth arrest both in-vitro and in-vivo. QQs, QSIs and EPIs compounds has been validated with various animal models for high selection pressure on therapeutics arsenal against microbe’s growth inhibition. Promising QSI are phytochemicals and secondary metabolites includes polyacetylenes, alkaloids, polyphenols, terpenoids, quinones.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Kothandapani Sundar, Ramachandira Prabu and Gopal Jayalakshmi"},{id:"82372",title:"Unlocking the Potential of Ghost Probiotics in Combating Antimicrobial Resistance",slug:"unlocking-the-potential-of-ghost-probiotics-in-combating-antimicrobial-resistance",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.104126",abstract:"Antimicrobial resistance is a global concern that requires immediate attention. Major causes of development of antimicrobial resistance in microbial cells are overuse of antimicrobials along the food chain especially in livestock, in preventing infections as well as misuse of antimicrobials by patients. Probiotics could be a viable alternative to antibiotics in the fight against antimicrobial resistance. Probiotic strains can act as a complement to antimicrobial therapy, improving antimicrobial function and enhancing immunity. However, there are safety concerns regarding the extensive use of live microbial cells especially in immunocompromised individuals; these include microbial translocation, inhibition of other beneficial microorganisms and development of antimicrobial resistance, among other concerns. Inevitably, ghost probiotics have become the favored alternative as they eliminate the safety and shelf-life problems associated with use of probiotics. Ghost probiotics are non-viable microbial cells (intact or broken) or metabolic products from microorganisms, which when administered in adequate amounts have biologic activity in the host and confer health benefits. Ghost probiotics exert biological effects similar to probiotics. However, the major drawback of using ghost probiotics is that the mechanism of action of these is currently unknown, hence more research is required and regulatory instruments are needed to assure the safety of consumers.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Abigarl Ndudzo, Sakhile Ndlovu, Nesisa Nyathi and Angela Sibanda Makuvise"},{id:"82178",title:"Managing Antimicrobial Resistance beyond the Hospital Antimicrobial Stewardship: The Role of One Health",slug:"managing-antimicrobial-resistance-beyond-the-hospital-antimicrobial-stewardship-the-role-of-one-heal",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.104170",abstract:"Infections caused by micro-organisms affect the health of people and animals, causing morbidity and mortality, with Asia and Africa as the epicenters. Some of the infectious diseases are emerging and re-emerging in nature. Examples include viral hepatitis, Lassa fever, Ebola, yellow fever, tuberculosis, covid-19, measles, and malaria, among others. Antimicrobials have been playing an important role in the treatment of infections by these microbes. However, there has been a development of resistance to these antimicrobials as a result of many drivers. This write-up used secondary data to explore the management of antimicrobial resistance (AMR) beyond the hospital antimicrobial resistance steward using the one health concept. The findings showed AMR to be a transboundary, multifaceted ecosystem problem affecting both the developed and developing countries. It is also one of the top ten global public health threats facing mankind. Globally, AMR will cost over US$100 trillion in output loss by 2050, about 700,000 deaths a year, and 4,150,000 deaths in Africa by 2050. About 2.4 million people could die in high-income countries between 2015 and 2050 without a sustained effort to contain AMR. The drivers of AMR are beyond the hospital and hospital AMR stewardship. Therefore, the need for one health concept to manage it.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Istifanus Anekoson Joshua, Mathew Bobai and Clement Sokfa Woje"},{id:"81918",title:"Machine Learning for Antimicrobial Resistance Research and Drug Development",slug:"machine-learning-for-antimicrobial-resistance-research-and-drug-development",totalDownloads:56,totalDimensionsCites:0,doi:"10.5772/intechopen.104841",abstract:"Machine learning is a subfield of artificial intelligence which combines sophisticated algorithms and data to develop predictive models with minimal human interference. This chapter focuses on research that trains machine learning models to study antimicrobial resistance and to discover antimicrobial drugs. An emphasis is placed on applying machine learning models to detect drug resistance among bacterial and fungal pathogens. The role of machine learning in antibacterial and antifungal drug discovery and design is explored. Finally, the challenges and prospects of applying machine learning to advance basic research on and treatment of antimicrobial resistance are discussed. Overall, machine learning promises to advance antimicrobial resistance research and to facilitate the development of antibacterial and antifungal drugs.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Shamanth A. Shankarnarayan, Joshua D. Guthrie and Daniel A. Charlebois"},{id:"81891",title:"Alternatives to Antibiotics in Semen Extenders Used in Artificial Insemination",slug:"alternatives-to-antibiotics-in-semen-extenders-used-in-artificial-insemination",totalDownloads:29,totalDimensionsCites:0,doi:"10.5772/intechopen.104226",abstract:"Antimicrobial resistance is a serious global threat requiring a widespread response. Both veterinarians and medical doctors should restrict antibiotic usage to therapeutic use only, after determining the sensitivity of the causal organism. However, the addition of antibiotics to semen extenders for animal artificial insemination represents a hidden, non-therapeutic use of antimicrobial substances. Artificial insemination for livestock breeding is a huge global enterprise with hundreds of million sperm doses prepared annually. However, reporting of antimicrobial resistance in semen is increasing. This review discusses the consequences of bacteria in semen samples, as well as the effect of antimicrobial substances in semen extenders on bacteria in the environment and even on personnel. Alternatives to antibiotics have been reported in the scientific literature and are reviewed here. The most promising of these, removal of the majority of bacteria by colloid centrifugation, is considered in detail, especially results from an artificial insemination study in pigs. In conclusion, colloid centrifugation is a practical method of physically removing bacteria from semen, which does not induce antibiotic resistance. Sperm quality in stored semen samples may be improved at the same time.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Jane M. Morrell, Pongpreecha Malaluang, Aleksandar Cojkic and Ingrid Hansson"},{id:"81699",title:"Efflux Pumps among Urinary E. coli and K. pneumoniae Local Isolates in Hilla City, Iraq",slug:"efflux-pumps-among-urinary-e-coli-and-k-pneumoniae-local-isolates-in-hilla-city-iraq",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.104408",abstract:"Urinary tract infections (UTI) are the most common bacterial infections affecting humans. Escherichia coli and Klebsiella pneumoniae were common enterobacteria engaged with community-acquired UTIs. Efflux pumps were vital resistance mechanisms for antibiotics, especially among enterobacteria. Overexpression of an efflux system, which results in a decrease in antibiotic accumulation, is an effective mechanism for drug resistance. The ATP-binding cassette (ABC) transporters, small multidrug resistance (SMR), and multidrug and toxic compound extrusion (MATE) families, the major facilitator superfamily (MFS), and the resistance-nodulation- cell division (RND) family are the five superfamilies of efflux systems linked to drug resistance. This chapter highlights the results of studying the prevalence of efflux pump genes among local isolates of E. coli and K. pneumoniae in Hilla City, Iraq. class RND AcrAB-TolC, AcrAD-TolC, and AcrFE-TolC genes detected by conventional PCR of E. coli and K. pneumoniae respectively. The result revealed approximately all studied efflux transporter were found in both E. coli and K. pneumoniae in different percentages. Biofilm formation were observed in 50(100%) of K. pneumoniae and 49(98%) of E. coli isolates were biofilm former and follow: 30(60%), 20(40%) were weak, 12(24%), 22(44%) were moderate and 7(14%) and 8(16%) were Strong biofilm former for E. coli and K. pneumoniae, respectively.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Hussein Al-Dahmoshi, Sahar A. Ali and Noor Al-Khafaji"}],onlineFirstChaptersTotal:13},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:126,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:13,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"August 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. His research interests include biomaterials, nanomaterials, bioengineering, biosensors, drug delivery systems, and tissue engineering.",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:27,paginationItems:[{id:"83092",title:"Novel Composites for Bone Tissue Engineering",doi:"10.5772/intechopen.106255",signatures:"Pugalanthipandian Sankaralingam, Poornimadevi Sakthivel and Vijayakumar Chinnaswamy Thangavel",slug:"novel-composites-for-bone-tissue-engineering",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biomimetics - Bridging the Gap",coverURL:"https://cdn.intechopen.com/books/images_new/11453.jpg",subseries:{id:"8",title:"Bioinspired Technology and Biomechanics"}}},{id:"82800",title:"Repurposing Drugs as Potential Therapeutics for the SARS-Cov-2 Viral Infection: Automatizing a Blind Molecular Docking High-throughput Pipeline",doi:"10.5772/intechopen.105792",signatures:"Aldo Herrera-Rodulfo, Mariana Andrade-Medina and Mauricio Carrillo-Tripp",slug:"repurposing-drugs-as-potential-therapeutics-for-the-sars-cov-2-viral-infection-automatizing-a-blind-",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Molecular Docking - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}},{id:"82582",title:"Protecting Bioelectric Signals from Electromagnetic Interference in a Wireless World",doi:"10.5772/intechopen.105951",signatures:"David Marcarian",slug:"protecting-bioelectric-signals-from-electromagnetic-interference-in-a-wireless-world",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biosignal Processing",coverURL:"https://cdn.intechopen.com/books/images_new/11153.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}},{id:"82586",title:"Fundamentals of Molecular Docking and Comparative Analysis of Protein–Small-Molecule Docking Approaches",doi:"10.5772/intechopen.105815",signatures:"Maden Sefika Feyza, Sezer Selin and Acuner Saliha Ece",slug:"fundamentals-of-molecular-docking-and-comparative-analysis-of-protein-small-molecule-docking-approac",totalDownloads:29,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Molecular Docking - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}}]},overviewPagePublishedBooks:{paginationCount:12,paginationItems:[{type:"book",id:"6692",title:"Medical and Biological Image Analysis",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6692.jpg",slug:"medical-and-biological-image-analysis",publishedDate:"July 4th 2018",editedByType:"Edited by",bookSignature:"Robert Koprowski",hash:"e75f234a0fc1988d9816a94e4c724deb",volumeInSeries:1,fullTitle:"Medical and Biological Image Analysis",editors:[{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}]},{type:"book",id:"7218",title:"OCT",subtitle:"Applications in Ophthalmology",coverURL:"https://cdn.intechopen.com/books/images_new/7218.jpg",slug:"oct-applications-in-ophthalmology",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Michele Lanza",hash:"e3a3430cdfd6999caccac933e4613885",volumeInSeries:2,fullTitle:"OCT - Applications in Ophthalmology",editors:[{id:"240088",title:"Prof.",name:"Michele",middleName:null,surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza",profilePictureURL:"https://mts.intechopen.com/storage/users/240088/images/system/240088.png",biography:"Michele Lanza is Associate Professor of Ophthalmology at Università della Campania, Luigi Vanvitelli, Napoli, Italy. His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. 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I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"117248",title:"Dr.",name:"Andrew",middleName:null,surname:"Macnab",slug:"andrew-macnab",fullName:"Andrew Macnab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. Gonzalez-Sanchez",slug:"juan-a.-gonzalez-sanchez",fullName:"Juan A. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. 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She created the research group in applied biochemistry in 2017 (https://web.ua.es/en/appbiochem/), and from 1999 to the present has made more than 200 contributions to Spanish and international conferences. Furthermore, she has around seventy-five scientific publications in indexed journals, eighty book chapters, and one patent to her credit. Her research work focuses on microbial metabolism (particularly on extremophile microorganisms), purification and characterization of enzymes with potential industrial and biotechnological applications, protocol optimization for genetically manipulating microorganisms, gene regulation characterization, carotenoid (pigment) production, and design and development of contaminated water and soil bioremediation processes by means of microorganisms. This research has received competitive public grants from the European Commission, the Spanish Ministry of Economy and Competitiveness, the Valencia Region Government, and the University of Alicante.",institutionString:"University of Alicante",institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983"},editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",slug:"ana-isabel-flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",slug:"christian-palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},onlineFirstChapters:{paginationCount:18,paginationItems:[{id:"83041",title:"Responses of Endoplasmic Reticulum to Plant Stress",doi:"10.5772/intechopen.106590",signatures:"Vishwa Jyoti Baruah, Bhaswati Sarmah, Manny Saluja and Elizabeth H. 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