Risk factors for DVT/PE.
\r\n\tAbout 25 percent of all foods produced globally are lost due to microbial growth. L. monocytogenes is a microorganism ubiquitously present in the environment and affects animals and humans. L. monocytogenes can enter a factory and is able to survive in biofilms in the food processing environment. The use of adequate sanitation procedures is a prerequisite in risk prevention. Moreover, effective control measures for L. monocytogenes are very important to food operators.
\r\n\r\n\tThe safety and shelf life maximizing of food products to meet the demand of retailers and consumers is a challenge and a concern of food operators.
\r\n\r\n\tTo obtain food systems more sustainable, several developments are ongoing to ensure safe food products with an extended shelf life and a reduction of food loss and waste. The problem of antimicrobial resistance is also a great issue that must be taken into consideration.
\r\n\r\n\tThe implementation of natural antimicrobials, using food cultures, ferments, or bacteriophages, is one approach to control L. monocytogenes in food products that meet the consumer preference for clean label solutions.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art about Listeria monocytogenes in terms of occurrence in humans, animals, and food-producing plants. Its control by more natural agents allows for more sustainable food systems and points future directions to transform challenges into opportunities.
Rabies, an RNA virus from the genus Lyssavirus, also known as RABV, is a lethal pathogen to several species [1]. The evolutionary history of the virus suggests that its most recent ancestor likely diverged into two descendants, one infecting bats, the other infecting dogs. Once domesticated dogs became infected in the Old World, humans became the next target. Evolutionary biology tells us that rabies likely did not exist in the New World prior to the settlement of Europeans but was common throughout Europe, Asia, and Africa well before the discovery of the Americas [2].
RABV is transmitted through the saliva of an infected individual into the bloodstream of a healthy individual, typically via a bite, but possible through other wounds or ocular route. Upon infection, there are two ways the virus may manifest: furious and paralytic. Furious rabies often presents itself with bouts of anxiety, irritability, phobias, and many other symptoms that will later be discussed. Paralytic rabies has some common symptoms with furious rabies, however, paralysis is the most notable symptom just prior to death [3].
According to the CDC in 2015, nearly 60,000 human deaths occurred on average each year. Statistically, this can be interpreted as 1 human death every nine minutes [4]. Despite its large impact globally, the virus is relatively diminutive. The rabies virus has evolutionarily reduced its single-stranded RNA genome to only five genes. These genes encode five proteins, three of which make up the ribonucleoprotein (RNP) complex; the other two form the virus’s envelope [5].
While the rabies virus has been heavily researched, lives continue to be lost. There is a great understanding of the epidemiology of the virus, however little is understood about the pathogenesis. Herein, the findings regarding the diagnosis, clinical course, treatment, and prevention of the rabies virus are summarized as well as data gaps in research and understanding of this pathogen.
Once the patient has become infected, the incubation period can be as short as 5 days or as long as 2 years. However, it is common for symptoms to occur 20–90 days after initial exposure [6]. Nevertheless, there are several techniques for diagnosing a patient during and after the incubation period.
As mentioned previously, the two ways the rabies virus may present itself is paralytic and furious symptoms. A patient with paralytic rabies will show progressive paralysis until death. If infection occurred due to a bite, the paralysis typically starts around the wounded area, spreading outwards. It is also common for patients to have a fever, vomiting, weakness in muscles, and myalgia prior to the paralysis [7].
Furious rabies often presents itself with more obvious symptoms. The infected individual commonly displays mood swings, unregulated consciousness, phobias, especially hydrophobia, as well as spasms of the respiratory system [1, 8]. Other symptoms may include a cough, psychosis, delirium, and difficulties swallowing [9].
For both furious and paralytic rabies, magnetic resonance imaging (MRI) will produce the same key diagnostic images. When symptoms first arise in the prodromal phase, progression in hypersignal T2 changes can be seen around the brachial plexus and the spinal nerve roots associated with the extremity of infection origin. The main MRI feature is increased T2 signal (seen on T2 and FLAIR sequences) in the affected parts of the brain and spinal cord, with a predilection for grey matter structures including basal ganglia, thalami, hypothalami, limbic system, and brainstem. The abnormal hypersignal T2 changes will continue to progress as the patient enters a coma. Once in the comatose phase, the contrast will enhance around the spinal cord, nerve roots located at the sine and cranial region, deep grey matter, brain stem, limbic structures, and thalamus (Figure 1) [8].
Magnetic resonance images with arrows pointing to high focal areas (A. dorsal medulla, B. pons, C. hypothalamus, and D. splenium of corpus callosum) of an infected patient with furious rabies [
Another study noted that lesions could be seen throughout different areas of the neuroaxis. They, too, found that paralytic and furious rabies present the same MRI indications, however, they are more noticeable in the paralytic form. The blood–brain barrier often shows no sign of damage until the patient reaches the comatose state. Imaging of the blood–brain barrier has greatly improved as new techniques such as diffusion-weighted and diffusion tensor imaging can capture objective and subjective data [11].
There are several techniques used to diagnose a patient with a rabies infection; including reverse transcription polymerase chain reaction (rtPCR) analysis, fluorescent antibody test (FAT), tissue culturing, and viral antibody neutralization [12, 13]. The FAT assay has long been a microbiological standard for diagnosing rabies (and other viral infections). Fluorescent antibody virus neutralisation (FAVN) test is also used to diagnose rabies [13]. The CDC recommends a direct form of FAT to detect the rabies virus in animals ante-mortem, however, the animal is usually euthanized after detection and brain tissue samples taken to solidify the diagnosis post-mortem. However, diagnosis in humans requires several different types of methods such as direct rapid immunohistochemistry testing, the use of electron microscopy, and reverse transcriptase-polymerase chain reactions on biological samples (Figure 2) [15].
These images show the comparison of a positive direct FAT result (left) and a negative direct FAT result (right) [
Another test utilizing immunohistochemistry, known as the direct rapid immunohistochemistry test (dRIT) is a specific form of histology because it employs antibodies unique to RABV. While this testing method can give a reliable result in less than an hour, retrieving brain samples is very invasive [16].
Samples can also be viewed using electron microscopy. When Negri bodies are located in samples, electron miscopy can give a clear depiction of the bullet-shaped rabies virus being produced. A colloid can be used to compare the virus size to further interpret the image, however shape and size alone are not enough to identify with confidence [17].
Saliva and skin samples can be used for identifying the presence of RABV. rtPCR can be used to confirm or oppose the results of FAT test results. Because RABV is a single-stranded RNA virus, rtPCR can help transform RNA into DNA through amplification for analysis of a complement to a rabies-specific primer. This is often achieved by inoculating suckling mice and retrieving brain or kidney samples after death [15, 18].
Given that the rabies virus significantly impacts the central nervous system, it is not uncommon for hallucinations, manic episodes, anxiety, and bouts of paranoia to be present in an infected patient [19, 20]. However, these are also common symptoms of psychiatric disorders such as schizophrenia. While it is rare, it is possible that correct RABV diagnosis may be complicated by a previous diagnosis of psychiatric disorders. Patients suffering from hypochondriasis could elicit psuedorabies [20]. In several case studies with reports of hypochondriasis, patients did not respond to therapies and often attempt suicide multiple times [20, 21]. While these situations are rare, they should be noted when diagnosing patients with certainty.
The most common entry point for RABV is through the bite of an infected individual as rabies resides in saliva [22]. However, transmission from organ transplants and aerosol droplets have also been recorded [23, 24, 25]. Upon entry, an incubation period often takes place in the myocytes, and rarely fibrocytes, where the virus attaches to the G-protein of the cells, enters through pinocytosis or fusion, and replicates in the cytoplasm of the cells [5, 24]. Virions will replicate with little to no immune response until the virus interacts with and infects a nerve cell. The rabies virus gains access to the nervous system by binding to the nicotinic acetylcholine receptors on the postsynaptic membrane at the neuromuscular junction [26]. From the point of nerve cell infection, the virus will travel via axon transport through the nervous system, eventually reaching the brainstem to give rise to either encephalitis or acute flaccid paralysis [7, 27]. The incubation periods are highly variable depending on the dosage of the virus. However, in humans, the incubation period is often >1–3 months. Canine incubation periods are most commonly less than 60 days [26, 28].
Once infection is recognized by the immune system, cytokine, IgM, and IgG antibody production increases [5]. Specific cytokines, Interleukin-1β (IL-1β) and TNFα, are thought to be the reason inflammation of the central nervous system occurs post-exposure [29]. The presence of these cytokines initiate a cascade reaction, upregulating proteins necessary for the inflammatory response such as the major histocompatibility complex and adhesion molecules. These proteins then interact with leukocytes to allow the blood brain barrier to become more permeable, thus causing an immune response leading to encephalitis [30]. As for the natural defense against rabies, RABV signals a series of molecular cascades that initiates type I interferon responses that have antiviral properties, decreasing the pathogenicity of rabies [31]. However, to artificially aid the natural response, there is heavy research on the potential to activate dendritic cells which subsequently enhance the activity of interleukin proteins and high mobility group box 1 (HMBG1) to enhance immunogenicity [32, 33].
Although the rabies disease has been documented for thousands of years, it is still largely considered incurable after the onset of symptoms [34]. This is due to the small window of time during which aggressive treatment is practical and effective. With that knowledge, most often treatment resolves to be mostly palliative with aggressive treatment proving to be essentially ineffective after RABV is established in the patient.
If a patient presents for treatment early in the process of the clinical disease, the choice may be made to apply an aggressive approach. At this point, the patient must be immediately admitted to an intensive care hospital and post-exposure prophylaxis (PEP) should be administered [26]. PEP consists of immediate washing of the wound with soap and water, a post-exposure vaccination, and injection of an anti-rabies immunoglobulin (RIG) directly into the wound [35].
Active immunization has evolved greatly since the first rabies vaccine was developed and administered in 1885 [36, 37]. Louis Pasteur is credited with this first vaccine that consisted of injecting the patient with homogenates of RABV-infected rabbit spinal cord multiple times over a period of days. The initial injection was believed to be fully inactivated after an extended desiccation period, and each subsequent inoculation was increasingly more virulent as the desiccation period was decreased. While this was found to be somewhat effective, two major issues presented themselves. First, the inactivation of the RABV was inconsistent which led to some patients becoming infected after receiving the vaccine. Second, there was an inequity in the supply of the RABV-infected rabbits and the demand of the human population. These were rectified with the introduction of RABV-infected sheep and goat brain vaccines [36, 37]. These new vaccines were inactivated via chemical agents such as phenol; this proved to be much more consistent. However, soon it was understood that vaccines produced from mature brain material contained an excess of myelin which caused sensitization and ultimately killed the patients [38]. From this discovery emerged the current methodology by which rabies vaccines are created. Chick embryos served the same role as the previous tissues, but they have markedly less myelin due to the young age [39]. The same can be said of the lines of human diploid cells infected with fixed RABV for vaccines [36, 37]. In the United States, there are two CDC-approved vaccines: the human diploid cell culture vaccine (HDCV) and the purified chick embryo cell culture vaccine (PCECV) [15].
The post-exposure vaccine is primarily an intramuscular vaccine that ought to be given on day 0, 3, 7, 14, and 30 [36]. An intradermal vaccine has recently been developed in an attempt to decrease the amount of vaccine needed per injection [40]. While the decreased cost of the vaccine is an attractive option, intradermal injections are generally considered more difficult which could decrease the effectiveness of the vaccine due to improper injections. The World Health Organization (WHO) strongly recommends purified cell culture and embryonated egg-based vaccines [41].
Although the vaccines have been proven to stimulate an appropriate immune response to RABV, this immune response is often too delayed to prevent the virus from entering the nerves [42]. With this knowledge, passive immunization is recommended for all patients that have no previous history with the disease or a pre-exposure vaccination. At this time, two types of rabies immunoglobulin are available – human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). These have been used since the 1970’s to temporarily increase the concentration of rabies virus neutralizing antibodies (RVNA) specifically at the site of exposure [43]. If the patient has multiple bites or wounds, the RIG needs to be applied at each site to be effective [44]. HRIG is to be administered at a dosage or 20 IU/kg while the recommended dosage for ERIG is 40 IU/kg [42, 44]. Due to higher odds of sensitization as well as quicker elimination of the RVNA, HRIG is generally the most preferred option for passive immunization. However, it is approximately five times more expensive than ERIG. This results in a major deficiency in many of the countries most in need of rabies treatment [44].
Because the available RIGs are generally inaccessible to developing countries, WHO encouraged researchers to pursue synthetization of a human monoclonal antibodies (mAbs) cocktail that can be used to treat rabies [45]. At this time, there are a number of rabies mAbs products in clinical trials, but none have been approved by the US Food and Drug Administration [46]. In 2018, WHO officially adjusted their recommendations for treatment of rabies to include mAbs products in place of RIG if available [46].
A protocol known as the Milwaukee Protocol was presented as a potential cure in the late 20th century, but it has since been proven to be inconsistent and generally ineffective in reverting or curing the patient of the disease [47, 48, 49]. This protocol consisted of an induced coma and one or more antivirals. The coma was soon determined to be ineffective. It is now recommended that sedation should be limited to prevent the use of ventilatory support if possible [48, 49].
Antivirals could serve an important role in the treatment of the rabies virus as they act as inhibitors of viral replication. An effective antiviral could slow the progression of the rabies virus enough for the patient’s innate immune response to develop and react appropriately. However, at this time, there are few antivirals supported for the treatment of RABV. Ribavirin is a purine analogue that acts as an RNA mutagen and has shown to be clinically effective for multiple viruses including Hepatitis C and Lassa fever virus [50, 51]. Despite its inclusion in the sporadically effective Milwaukee Protocol, it has repeatedly proven to be ineffective against the rabies virus. Interferon-α (IFN-α) is a signaling protein used to trigger an immune response which has been shown to limit RABV spreading in mice trials [50, 51]. However, additional trials in which primates were administered intramuscular and intrathecal IFN-α determined the effects of immediate inoculation to be incomplete while the effects of delayed inoculation were nonexistent [52, 53]. Six human patients have been treated with IFN-α on two different dosage schedules and despite evidence of increased IFN in serum and CSF, there was no evidence of a beneficial effect on the disease itself [54]. Another therapy previously included in the Milwaukee Protocol is ketamine [50, 51]. At low concentrations, approximately 1 μM, ketamine works as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor which causes a state of dissociative anesthesia. A study from 1991 showed that a high concentration of ketamine could induce inhibitory effects on the RABV genome transcription [55]. Since that time, multiple other trials using neuron cultures and infected mice have produced evidence that ketamine is generally ineffective against the disease [56]. With that knowledge, it is believed that ketamine should not be used for treatment of the rabies virus until further studies produce more promising results. Amantadine is the third and final antiviral that was considered in the Milwaukee Protocol [47, 51]. It is a synthetic inhibitor of viral replication by impeding the release of viral genetic material into the host cell. Although amantadine demonstrated some interference in cellular trials, it failed in animal trials [57]. Minocycline, a broad spectrum antimicrobial, was considered for RABV treatment as it has proven benefits for multiple other viruses [58]. However, when applied to rabies-infected animals, Minocycline caused a number of harmful effects causing an increase in mortality [59].
More recently, researchers have addressed the use of favipiravir in treatment of rabies [50]. Available for influenza treatment in some countries, favipiravir has shown some activity against the rabies virus in mice trials [60]. Continued studies are needed to assess the future of this and other antivirals. It ought to be noted that despite variations in the effectiveness of these antivirals, all have shown that an early start of treatment greatly improves the efficacy of these therapies.
As previously mentioned, there is a small window of effectiveness for an aggressive treatment of RABV; after that window has passed, the focus of treatment is purely one of comfort for the patient. Many patients develop phobias that will likely require seclusion in a calm, quiet room. Although there is little to no evidence of human-to-human transmission, visitors and medical professionals need to be cautious of potential contamination via the patient’s secretion [61]. Dehydration is a major concern as paralytic rabies often inhibits the patient’s ability to swallow and furious rabies can cause intense hydrophobia. Treatment for the dehydration is typically a secured intravenous line. If additional nutrients are needed, they can be administered through the same line.
Rabies typically causes a generalized inflammation that induces a fever, but it can also trigger a neurogenic (central) fever as well [62]. Many antipyretics, such as acetaminophen and ibuprofen, have been successfully used to treat the generalized fever. However, those are generally ineffective towards the central fever. There is some evidence to support the use of baclofen, bromocriptine, chlorpromazine, and morphine in the treatment of a central fever [63]. However, these have not been studied specifically for a rabies-induced central fever and so practitioners should be mindful of potential side effects. Additionally, these drugs are rarely available in the developing countries where RABV is most prevalent [61]. In this case, external, physical means of cooling the patient can be used as needed.
The majority of patients infected with furious RABV develop intense agitation and fear. A variety of sedatives and tranquilizers are used to calm these symptoms. Because benzodiazepines are included on the WHO’s list of essential medicines, they are commonly used to treat rabies-induced agitation as well as many other forms [61]. They can be administered intramuscularly, intravenously, or intrarectally as needed. However, as previously mentioned, it is important to administer any sedative slowly to ensure the patient retains consciousness and does not lose respiratory function [64].
Lastly, clinicians will likely need to address the patient’s pain level. This can be accomplished using opioids such as morphine or other highly effective analgesics. These can be delivered intravenously, intramuscularly, intrarectally, or even transdermally as needed [61]. Although many of these methods of treatment are expensive and generally unlikely to cure a patient once rabies symptoms are present, palliative care is a responsibility of caretakers and clinicians.
Due to the general ineffectiveness of post-exposure treatment, the rabies virus has a remarkably high mortality rate despite the availability of vaccines that have shown a near perfect success rate when administered prior to infection. This indicates that the main issue with prevention is the lack of accessibility in the impoverished countries of Asia and Africa. In 2015, the World Health Organization (WHO) and the World Organization for Animal Health (OIE) with the help of the Food and Agriculture Organization of the United Nations (FAO) set a goal to rid the world of dog-mediated rabies by 2030 (Zero by 30) [65]. After assessing cost and general accessibility, it was decided that the best way to eliminate dog-mediated rabies is to vaccinate dogs rather than humans. Vaccinating at least 70% of dogs should effectively break the cycle of rabies transmission.
To reach this goal, WHO, OIE, FAO and many smaller agencies collaborated to create the Stepwise Approach towards Rabies Elimination (SARE) [66, 67]. A similar stepwise approach proved successful in the elimination of fox RABV from Europe [68]. SARE consists of five stages for each country to work through. Stage 0 is simply the lack of information and data on RABV cases in a country where rabies is believed to be present. Stage 1 is an assessment phase in which data are gathered to determine the extent to which RABV pervades the country of interest. During this phase, the government assesses the current guidelines or structures in place as well as collects and analyzes all available data on previous or existing RABV cases. The beginning of an action plan is usually concocted in Stage 1. Evolution of this plan happens in Stage 2; it is important to develop an understanding of the available funding at this point as that has been the biggest limitation for developing countries in the past. Stage 3 is the implementation of the country’s rabies control strategy. During this phase, the plan will likely need to be adapted to address any challenges that arise; these may include the exposure of wildlife reservoirs of RABV such as the fox rabies previously found in Europe. When reported human cases have decreased to zero, the country will shift into Stage 4 – elimination of dog RABV. This requires the maintenance of the reduced dog-to-human rabies transmission as well as continued implementation of the action plan to continue to reduce dog rabies cases. Lastly, in Stage 5, the country must develop a post-elimination strategy to maintain the freedom from human and dog rabies.
While the SARE tool has been developed to be adaptable enough to succeed worldwide, there are likely to be some setbacks in the different landscapes. Specifically, areas of poverty will be constrained by the financial resources they can acquire. Many parts of Asia have political instability that will greatly challenge the need for nation-wide commitment to this goal. Similarly, Africa’s linguistic and cultural complexity will oppose the need for excellent communication and tracking [66]. Ultimately, it will take a dedicated and educated global population to eliminate rabies as a whole; until then, vaccinating animals and at-risk populations is the most efficient means of prevention.
This chapter served to outline the diagnosis, clinical course, treatment, and prevention of the RNA virus RABV. A swift rabies’s diagnosis is imperative to ensure the patient’s greatest chance of survival. Clinicians may utilize many techniques such as MRI, rtPCR, FAT, FAVN, dRIT, and electron microscopy to diagnose patients before physical symptoms arise. The same methods can be used to confirm a diagnosis after the patient presents with symptoms if needed. Rabies can present in patients in the furious or paralytic form. Although these cause very different physical symptoms, the pathophysiology is very similar. Generally initiated by a bite or other wound, the virus will incubate in the myocytes nearest the entry point and replicate undetected for an average of 1–3 months. Eventually, the virus will infect a nerve cell and travel through axon transport to the CNS at which point it will cause encephalitis or paralysis. Once the virus has infiltrated the CNS, it is essentially incurable. However, if detected early, patients can receive PEP - a combination of active and passive immunization most frequently in the form of a cell culture vaccine and a dose of RIG. At this time, there are no antivirals considered to be effective for treating RABV. If the virus becomes established in the patient, the treatment plan is adjusted to ensure the most comfort for the patient and their loved ones. This most often consists of a variety of sedatives, pain management, antipyretics, and fluids. Due to the great lethality of RABV in humans, multiple global organizations have banded together to attempt to eradicate the modern world of the rabies virus. The Zero by 30 movement strives to implement a stepwise method to eliminate dog-mediated rabies cases worldwide by 2030. This is believed to be possible if 70% or more of the dog population is vaccinated against rabies. In combination with the vaccination goal, Zero by 30 also encourages countries to implement educational standards on rabies, bite prevention, and responsible pet ownership.
At this time, the community of RABV researchers need to be working to improve current treatment options in order to decrease the number of RABV-related deaths. This might be done by developing a mAb alternative to the too-expensive RIG options or finding an effective antiviral either currently on the market or newly developed. The release of additional rabies vaccines for humans would also help to lower the price and improve the accessibility in a way that would benefit the highly affected countries.
The authors declare no conflict of interest.
Acute Pulmonary embolism (PE) is an emergency. It needs immediate clinical evaluation for appropriate recognition due to the availability of appropriate therapeutic interventions to decrease its immediate mortality and avoid postthrombotic complications. Clinical manifestations of a patient coupled with the risk factors at initial presentation should guide to PE suspicion. In cases where the clinical scenario is not straightforward, multiple algorithmic score models should promptly guide the physician to diagnose PE. PE diagnosis is accomplished with the help of multiple imaging studies, of which chest computed tomography (CT) is the one used frequently. In this topic, we will glean over all the factors that help in diagnosing an acute PE.
Acute pulmonary embolism (PE) is an acute critical clinical condition characterized by the propagation of blood clots from peripheral veins or systemic circulation to the lung vasculature affecting the alveolar gas exchange. Acute PE can be symptomatic or silent. The thrombus responsible for PE often originates from leg veins, especially the deep calf veins, followed by proximal dispersion to popliteal and femoral veins [1]. Thrombus at popliteal vein and proximal to it are at a high risk of embolic phenomenon resulting in acute PE. A non-propagating deep calf vein thrombus increases recurrence rate and the likelihood of postphlebitic complication [2]. A thrombus from the upper extremity is often due to intravascular venous catheters, cardiac devices, effort thrombosis, or thoracic outlet obstruction [3]. Pelvic veins represent another source of emboli in patients with recent pelvic surgery, pregnancy, infection, or prostate disease. Rarely pulmonary vascular occlusion occurs due to nonthrombus etiology such as parasites (schistosomiasis), sickled erythrocytes (sickle cell disease), talc (illicit drugs), air (central lines), or tissue (amniotic fluid or fat embolism).
Earlier clinical literature suggested PE as an underdiagnosed condition; however, recent studies indicate it to be an excessively diagnosed condition due to the introduction of modern imaging techniques in detecting PE [4, 5]. Newer studies indicate an increased incidence at >113 cases per 100,000 population [5]. Another reason is defensive medicine, as the inability to identify a clinically symptomatic patient could turn out to be a malpractice issue as only 8% die with appropriate therapy, and the figure is 30% with no therapy [6, 7, 8]. Even with an increased incidence, the overall mortality rate has remained the same, declining case fatality rates [5]. The DVT/PE incidence rate in the United States of America (USA) yearly is 600,000 patients per year [9]. Approximately 30% of these patients die within the next 3 months (180,000 per year) [4]. In medical or surgical intensive care units (MICU/SICU), deep vein thrombosis (DVT) occurs in 30% of patients [10, 11]. In an extensive registry of diagnosed DVT patients, PE was seen in 29% in the lower extremity(LE) and 9% in the arms [12]. PE occurrence was similar in these groups on observing them over the next 90 days. PE is a frequent preventable mortality source in hospitalized patients [13]. Despite anticoagulant therapy in critically ill, acute PE is linked with considerable morbidity and mortality due to a limited cardiopulmonary reserve [14]. After the acute critical episode, patients who make it out are at higher risk of type four pulmonary hypertension and postthrombotic syndrome. A recent study confirms that after 6 months of a PE episode, dissolution of the entire clot was observed in 50% of patients, and the remaining still had lingering occlusion [15, 16].
Symptomatic patients with acute respiratory failure should increase diagnostic possibility if they have risk elements. These risk factors have been mentioned in Table 1 [1, 13, 14].
Acquired | Inherited |
---|---|
1. Factor V Leiden mutation | |
Bed rest due to hospitalization or stroke | 2. Prothrombin gene mutation |
Air travel | 3. Antithrombin III deficiency |
Post-operative: Hip/Knee/Trauma/Spinal | 4. Protein C deficiency |
Morbid Obesity | 5. Protein S deficiency |
Comorbidities: Heart failure, Obstructive lung disease, elderly, prior stroke | 6. Dysfibrinogenemia |
Pregnancy/Postpartum | |
Oral contraceptives | |
Hormonal replacement therapy | |
Polycythemia vera, Essential thrombocytosis | |
Leukemia, Paroxysmal Nocturnal Hemoglobinuria | |
Antiphospholipid antibody syndrome | |
Nephrotic syndrome, Inflammatory Bowel disease | |
Malignancy |
Risk factors for DVT/PE.
Clinical features depend on the patient’s physiologic response to the venous thrombus, especially cardiopulmonary reserve, and vary from asymptomatic to hemodynamic instability and death. An excellent clinical history can reveal risks, including hormone replacement therapy, bed rest, air or road travel, oral contraceptive use, and other comorbid conditions. Clinical symptoms include acute respiratory distress (most common), chest discomfort, dry cough, fever, leg swelling with or without pain, bloody expectoration, and rarely syncopal episode. The physical examination can reveal tachycardia, tachypnea, hypotension, phlebitis, rales, a loud P2, and an S4. It may also reveal other signs indicative of risk factors. Of the above clinical features, only three can distinguish between positive and negative PE based on angiogram, including rales, a loud P2, and S4 [17]. Clinical presentation to a hospital is seen via five different syndromes, which include 1) Pleuritic chest discomfort or bloody expectoration, 2) Shortness of breath only, 3) Hemodynamic instability, 4) Subclinical clot, 5) Chronic non-resolving clot [1, 17]. The fourth and fifth clinical syndrome may be identified incidentally on the imaging studies while working for dyspnea of unknown origin or as a study to rule out other clinical conditions.
A complete blood cell count can disclose leukocytosis, while a peripheral smear and a differential count can reveal leukemia, myeloproliferative disorders, or other hematological conditions. NLR (Neutrophil to lymphocyte ratio) and PLR (platelet to lymphocyte ratio) if elevated at PE diagnosis signify an elevated short-term risk and overall mortality; however, the exact cutoff for NLR and PLR is yet to be decided. Both NLR and PLR can serve as cheap prognostic indicators in acute PE [18]. Acute PE causes myocardial distension and stretching, leading to an increase in BNP (Brain Natriuretic Peptide) and NT-proBNP (N-terminal pro-brain Natriuretic Peptide). The right ventricle (RV) undergoes significant strain during an acute massive PE, resulting in RV ischemia that can be small and cause elevated troponin and H-FABP (heart-type fatty acid-binding protein levels). Elevated above-mentioned cardiac biomarkers and troponin in nonmassive PE signify higher short-term mortality and PE-related adverse events [19, 20]. Also, in nonmassive PE, RV dysfunction correlated appropriately with short-term mortality [20]. Arterial blood gases (ABG) reveal hypoxemia in acute PE, which can worsen with increased PE size. PE leads to increased dead space ventilation and hypercapnia; however, this is seen in patients with limited ventilatory reserve or mechanically ventilated patients [1]. In an earlier study, a 100% NPV (negative predictive value) for PE correlated with respiratory rate < 20 per minute, normal D-dimer level, and partial pressure of oxygen ≥80 mmHg [21]. This was later found to have an NPV of 95% in a more extensive study where multiple ABG prediction rules were assessed and were found to lack adequate NPV, likelihood ratios, or specificity [22]. Thus ABG has minimal conclusive value in suspected PE patients and is inadequate to diagnose or exclude PE.
D-dimer presence in blood indicates intrinsic fibrinolysis by plasmin. In DVT, D-dimer elevation is lesser than that seen in PE due to the smaller size of the thrombus. Thus D-dimer sensitivity is higher in PE (> 95%) than in DVT (>80%) [13]. The D-dimer elevation is observed in infection, inflammation, ischemia, cancer, trauma, and postoperatively making it a nonspecific test. Thus its predictive role in hospitalized patients is minimal. D-dimer is outstanding in patients <65 years of age plus lower pretest PE probability. D-dimer had a diminishing value in the patient subset >65 years of age due to more false positives [23]. Another study suggested using age-adjusted D-dimer testing alongside Well’s score as it improved efficiency with no effect on safety in all subgroups studied. The efficiency was notably observed in elderly patients, patients with cancer, obstructive lung disease, prior venous thromboembolism, or a late presentation [24]. A standardized hypersensitive negative test result safely rules out PE among mild or moderate-risk patients [1].
In a small proportion(10–25%) of PE patients an ECG (electrocardiogram) is normal [25]. ECG can reveal multiple findings that lack sensitivity and specificity individually to diagnose PE. The commonest ECG finding is acute sinus tachycardia [26]. Other significant ECG findings are mentioned in Table 2 below [27].
1. Acute sinus tachycardia |
2. T wave inversions in precordial leads (V1-V4) |
3. S1Q3T3 sign (Lead I S wave, Lead III Q wave, and a Lead III inverted T wave) |
4. Atrial arrhythmias |
5. RBBB (Right bundle branch block) |
6. Low amplitude QRS complexes |
7. ST-segment elevation in leads V1 and aVR |
8. Q wave (Leads III and aVF) |
ECG findings in acute PE.
In an established extensive PE, a frequent earlier finding is precordial T wave inversions [28]. The observation of S1Q3T3, RBBB, and inverted T waves (V1-V4 leads) in a PE patient’s ECG indicated RV dysfunction [28, 29]. V1 to V3 precordial lead T wave inversions had a higher true positive rate and diagnostic accuracy than S1Q3T3 and RBBB findings in RV dysfunction detection in acute PE [30]. If ECG reveals an RV strain pattern, the patient is at a higher mortality risk and adverse outcomes, despite being hemodynamically stable [31]. RBBB, Lead V1 ST-segment elevation, and low voltage QRS complexes are observed in PE patients with cardiogenic shock [32]. The following findings were frequently seen in patients who had a fatal outcome after a PE, including complete RBBB, atrial arrhythmias, Q wave (leads III & aVF), Peripheral small amplitudes, and left precordial ST changes. In a study, 29% of patients with these ECG findings did not make it out of the hospital on discharge [33]. A concurrent occurrence of inverted T waves in leads II, III, aVF, and V1 to V4 is highly distinct for PE (99%) than ACS but uncommon [34]. Acute PE accurately distinguishes from ACS by the presence of lead III and V1 T wave inversions on ECG [35]. An essential role of performing an EKG in acute PE is its help in ruling out other differential diagnoses, such as ACS, myocarditis, or acute pericarditis.
Venous duplex ultrasound uses the ability to detect venous blood flow and real-time B-mode images to identify clots in both upper and lower limbs [36]. The specific diagnostic DVT criteria include the following, lack of venous segment collapse on pressure (more specific), respiration induced loss of phase changes, a weak venous response to Valsalva, echogenic substance in the lumen, loss of increase in flow due to compression, and loss of flow or decreased flow on color Doppler [1]. In symptomatic patients, duplex ultrasonography sensitivity and specificity in diagnosing DVT are higher than in asymptomatic patients (lesser accuracy). While 30–40% of PE patients are clinically symptomatic for proximal DVT, the venous duplex can detect proximal DVT in 60–80% of PE patients [37]. In postoperative orthopedic patients, the performance of venous duplex ultrasound was comparable to contrast venography in asymptomatic proximal DVT detection [38]. Asymptomatic DVT in contralateral LE was seen in 5–10% of patients with acute symptomatic DVT [39]. Duplex ultrasonography accuracy in identifying deep calf vein limited DVT, and asymptomatic proximal vein DVT is limited in high-risk populations [40]. After an initially negative result in suspected DVT patients, serial duplex ultrasonography can detect the proximal extension [41].
The sensitivity of detecting PE via TTE (transthoracic echocardiogram) is only 50%, so it is a poor imaging modality for acute PE diagnosis [42]. RV pressure or volume overload suggestive of PE can guide PE diagnostic imaging without other differentials [1]. TTE can reveal the McConnell sign (RV mid-free wall lack of movement with no apex involvement) [43]. On rare occasions, emboli can be visualized in the right heart on TTE. TTE based risk assessment helps in guiding acute PE therapy. Patients with RV dysfunction on TTE in a normotensive patient indicate adverse outcomes or early mortality [44, 45]. An appropriately done TEE (transesophageal echocardiogram) can detect central PE (Pulmonary artery and its branches) with a true positive and negative rate > 90% [46]. It is an excellent modality to consider in a speculated massive PE patient hemodynamically unstable for transport or has contrast contraindication. TTE helps ward off other differential diagnoses, including infective endocarditis, pericardial effusion or tamponade, aortic dissection, and RV myocardial infarction. Significant changes seen on a TTE are mentioned below in Table 3 [47].
1. Increased ventricle size ratio |
2. Abnormal septal motion |
3. Tricuspid valve regurgitation (TVR) |
4. 60/60 sign |
5. McConnell’s sign |
6. Right heart thrombus |
7. Right ventricle hypokinesis |
8. Pulmonary hypertension |
9. Increased right ventricle end-diastolic diameter (RVEDD) |
10. Tricuspid annular plane systolic excursion (TAPSE) |
11. Increased right ventricle systolic pressure (RVSP) |
Distinct TTE signs seen in acute PE.
A meta-analysis assessed multiple echo studies and consistently showed that TTE had a greater specificity and sensitivity for PE diagnosis and is a definitive rule in test at the bedside for suspected patients [47]. As per ACEP guidelines, the presence of an RV dysfunction on TTE in an unstable patient can suggest acute PE and an indication for thrombolytic therapy [48].
A positive or negative transthoracic lung ultrasound (TLS) can cause an increment or decrement in PE probability by 30% in a moderate risk population, which can change the diagnostic workup [49]. TLS can detect smaller PE in the periphery of the lungs [50]. Most emboli are observed in the lower lungs, which can be easily accessed by TLS [51]. An endobronchial ultrasound (EBUS) can detect central PE and immensely help PE patients with AKI, contrast contraindication, pregnancy, and hemodynamically unstable patients with diagnosis [52, 53, 54]. Simultaneously it can measure the acutely elevated pulmonary hypertension in patients with PE. Endobronchial ultrasound findings can supplement TLS in acute PE detection [49]. However, the resources required (regular bronchoscope, trained nursing staff) to perform a bedside bronchoscopy with EBUS makes it challenging to achieve in the emergency department or the MICU on an as-needed basis. Performing a bronchoscopy in a hemodynamically unstable patient may worsen the patient’s overall cardiopulmonary status and increase his high risk of adverse outcomes.
A meta-analysis revealed that cardiopulmonary ultrasound (CPUS) sensitivity was 91% and specificity was 81% for PE diagnosis in comparison to CT pulmonary angiography (CTPA) [55]. The BLUE (bedside lung ultrasound in emergency) protocol was made to diagnose PE based on a DVT positive venous duplex combined with TLS. It was 99% specific and 81% sensitive for PE diagnosis and ruled out other acute respiratory failure differentials [56]. BLUE protocol and TTE consistently revealed a greater specificity than sensitivity due to the lack of ruling PE out with no CTPA [56, 57]. The combination may help in decreasing the excessive CTPA done currently [58]. In resource-limited settings such as in developing countries or the absence of CTPA availability, CPUS may have a role in managing PE [55].
Chest X-ray can either be normal or abnormal. Most often, a chest X-ray reveals nonspecific abnormal findings such as effusion, infiltrates, or atelectasis. Certain signs with interesting names that have been observed on chest radiograph imaging are mentioned in Table 4 [59, 60, 61].
1. Westermark’s sign | Localized diminished blood supply in lung |
2. Hampton’s hump | Pulmonary infarction distal to occluded emboli (Wedge shape) |
3. Palla’s sign | Distended right descending pulmonary artery or sausage appearance |
4. Fleischner sign | Central pulmonary enlargement |
5. Knuckle sign | Abrupt pulmonary artery tapering |
Interesting findings noted on chest-X-ray.
The occurrence of Westermark’s sign and Palla’s sign suggests embolic obstruction of either the lobar/segmental pulmonary artery/widespread small arterial involvement [60]. A patient with acute shortness of breath, respiratory distress, or hypoxia and a benign chest radiograph is suspicious of possible PE. A chest radiograph also helps in ruling out other causes such as empyema, pneumonia, and pneumothorax.
After CTPA, V/Q (ventilation/perfusion) scintigraphy is an alternative utilized in diagnosis. V/Q scintigraphy negative or high-probability result is of critical value in PE diagnosis [62, 63]. A negative V/Q scan result is as efficacious as a pulmonary angiogram, ruling out acute PE and slightly better than a CTPA [64]. A normal perfusion scan sensitivity in ruling out PE is exceptional, observed even with a higher pretest PE probability in severely sick patients [62, 65, 66]. A meta-analysis validates this observation by revealing a minimal 0.3% PE incidence in individuals with an intact perfusion result [67]. Similarly, high-risk V/Q scintigraphy (multi-segmental mismatch defects) correlates with acute PE in 87% of patients, and the positive predictive value (PPV) is increased to 96% by a higher pretest probability [62]. However, most suspected acute PE or PE patients do not have V/Q scan findings suggestive of a high probability scan. Also, most patients with no PE did not have a normal V/Q result. A clinically significant portion of patients (33% = moderate risk and 10% = low risk) had positive angiograms. The prospective trial PIOPED stressed on the number of perfusion defects and size along with a concurrent image to identify V/Q mismatch defects [62]. In the PISA-PED study, greater emphasis was placed on the perfusion defect shape than the number and size or ventilation image correlation [65]. The PISA-PED study confirmed that perfusion in combination with pretest probability in the absence of ventilation image could diagnose acute PE without angiography [65]. A majority of intermediate V/Q imaging results are observed in obstructive lung disease patients [68]. V/Q scintigraphy is favored in patients with renal failure, contrast allergy and offers similar diagnostic efficacy in pregnancy [1, 69]. The severely sick patients can undergo bedside perfusion imaging to avoid transportation-associated risks [1].
SPECT-V/Q scan, a new scintigraphy process that generates 3-dimensional images than a planar image seen in V/Q scans. Advantages associated are better visualization of all perfusion defects in different lung areas, less radiation exposure than CTPA, fewer nondiagnostic test results (0.5–3%) [70, 71, 72, 73, 74, 75]. SPECT-V/Q efficiency is similar to that of CTPA in suspected acute PE patients [76]. SPECT-V/Q true positive and negative rates were noted to be in the range of 95–100%. [76, 77]. However, it cannot replace CTPA as a test of choice in acute PE due to the lack of vigorous extensive testing to verify its validity in suspected patients [78]. Specific clinical scenarios might be appropriate for using a SPECT-VQ scan, including a nondiagnostic CTPA study and post-discharge evaluation of lingering perfusion abnormalities.
The imaging modality of choice to exclude acute PE in suspected patients is CTPA. CTPA sensitivity is 83%, specificity is 96%, with an NPV of 97% plus a PPV of 86% in suspected patients [17]. CTPA sensitivity and specificity are greater than 95% in central PE (pulmonary artery and lobar branches) [79]. The sensitivity and specificity decline gradually when the emboli involve segmental or subsegmental pulmonary arteries. In a study of CTPA for subsegmental artery, involvement sensitivity was noted in the range of 71–84% [80]. PE involving only the subsegmental arteries of the pulmonary circulation is seen in around 30% of PE patients [81, 82]. CTPA evaluation is diagnostic when emboli involve the main or lobar pulmonary arteries and is considered suggestive if the segmental and subsegmental pulmonary arteries are occluded. CTPA predictive value is critically hampered in discordance with clinical evaluation, and further imaging tests merit consideration in this scenario [1]. CTPA has its limitations which are significant to be ignored. Intravenous iodinated contrast given during CTPA can cause AKI. CTPA cannot effectively diagnose emboli in the subsegmental pulmonary arteries and cannot supplement the V/Q scan, which also lacks in this particular territory [62, 81]. CTPA is not able to identify whether the emboli is acute, subacute, or chronic. CTPA occurrence results in significant radiation exposure to the patient, especially in young females (breast and lungs) [83]. Clinical observations have suggested significant overuse of CTPA resulting in overdiagnosis of pulmonary embolism; however, it cannot determine whether the positive CTPA identifies acute PE, subacute PE, or chronic PE [63]. A clinical study observed no substantial difference in results when anticoagulation was withheld in suspected individuals with a normal CTPA plus negative leg duplex ultrasonography and negative or non-high probable V/Q imaging with a negative leg venous duplex [63]. The study was performed on relatively stable patients, so this observation cannot be utilized in severely sick patients or patients with inadequate cardiopulmonary reserve [84].
A clinical trial PIOPED III evaluated a magnetic resonance angiogram for PE diagnosis [85]. Overall, the sensitivity to diagnose a PE involving the main and lobar pulmonary artery was 79%. It may be an ideal test for patients with intravenous contrast allergy or to avoid radiation exposure, such as pregnancy.
CT venography (CTV) has similar diagnostic accuracy as venous duplex ultrasound for the LE in diagnosing or ruling out DVT; however, the test is invasive and comes with exposure to contrast and radiation [86]. In addition to the LE venous system, vena cava and pelvic veins are visualized. CTPA and CTV combined revealed a mild improvement in diagnostic outcome with a substantial increase in cost and pelvic exposure to radiation.
Contrast venography is the best imaging study for substantiating LE venous thrombosis. Its diagnostic criteria include a persistent venous filling defect observed in ≥ two views. It is an expensive, invasive test requiring clinical expertise and accurate interpretation with significant exposure to intravenous iodine contrast. Due to the above reasons, Venous duplex has replaced it as the test of choice to diagnose acute DVT.
Before CTPA, a pulmonary angiogram was the best imaging study to diagnose acute PE. It requires appropriate clinical expertise to perform the invasive procedure and interpret it. Three factors determine the result, including the location of the emboli, image quality, and interpreter’s experience [1]. Diagnosis of PE is indicated by either a filling defect and/or abrupt vessel cutoff. Flow defects can be avoided by ensuring good vascular opacification and obtaining multiple sequences of films. The PIOPED trial revealed that it was diagnostic in 97% of patients and associated with 1% complications, including a mortality rate of 0.5% [87]. Adverse outcomes were significantly seen in MICU patients transported for an angiogram. A pulmonary angiogram is considered in a tiny patient subset when PE diagnosis cannot be determined by noninvasive imaging studies, significant discordance between imaging study and clinical evaluation, and chronic thromboembolic disease.
The current clinical approach for acute PE or DVT diagnosis utilizes a Bayesian analysis. Here pretest probability of the clinical condition is measured exclusive of the test outcome wire clinical means or a consistent prediction rule such as Well’s or Geneva score. Then a posttest probability of the clinical condition is generated by utilizing pretest probability combined with a test’s likelihood ratio. The posttest probability is used as guidance for clinical decision making that confirms or to excludes the disease with a degree of probability or helps in deciding additional imaging studies. Clinical predictive rules for acute DVT include the Well’s, revised Well’s, and Geneva scores. Well’s score classifies suspected acute DVT patients into three subclassification’s unlikely (3%), moderate (17%), and likely (75%). With the help of Well’s score and LE venous duplex ultrasound, diagnosis of acute DVT can be established in likely individuals with a positive LE venous duplex result. In unlikely individuals, a negative LE venous duplex result excludes acute DVT [88]. The revised Well’s score divided the patients into likely and unlikely categories. The unlikely group with a negative D-dimer excluded an acute DVT without needing a LE venous duplex ultrasound [89, 90].
Clinical predictive tools for acute PE include Well’s criteria, revised Geneva score, Pisa model, PERC (PE rule-out criteria), and Charlotte rule [91, 92, 93, 94, 95]. Among the clinical predictor rules or scores for acute PE diagnosis, Well’s score fared better than the revised Geneva score [96]. Most diagnostic algorithms for acute PE use either CTPA or V/Q scintigraphy as a first test. A diagnostic algorithm based on clinical probability has been described in Figure 1 below for acute PE.
Diagnostic testing of acute PE based on clinical probability.
Clinical predictive rules or scores are not superior to clinical assessment but offset the variation observed with physician judgment and experience by standardization [1]. These rules were framed for patients seen in outpatient settings and applicable in primary care and emergency departments; however, they fare poorly and lack clinical validity in hospitalized patients. In hospitalized patients, the clinical predictive scores or rules and D-dimer are of minimal help to make a clinical decision. As a result, most of these patients need an imaging study to rule in or exclude acute PE diagnosis [1].
Although acutely ill patients are at a higher risk of acute PE, COVID -19 (coronavirus disease 2019) infected patients suffer from in situ immunothrombosis characterized by small and medium pulmonary artery numerous thrombi occurring at a greater frequency (24%) than in H1N1 influenza patients [97, 98, 99, 100, 101]. PE phenotype in COVID-19 patients in comparison to others correlates with peripheral thrombotic lesions with a lesser clot burden [102]. Pulmonary localized immunothrombosis in COVID-19 is a minimal addition to the overall procoagulant state resulting in DVT seen only in 42.4% of PE patients in COVID-19 than the 60% occurrence seen frequently in other PE patients [103]. D-dimer elevation in COVID-19 could be due to the acute infection-induced inflammation causing a procoagulant state or a localized micro thrombosis in the pulmonary vasculature.
D-dimer levels elevation >500 μg/L & 1000 μg/L were associated with a higher sensitivity (> 90%) but a lower specificity (< 30%) in PE diagnosis. D-dimer performance in COVID-19 is similar to that seen in other prothrombotic conditions [104]. COVID-19 patients on statin therapy before admission had a lower risk of PE occurrence [105]. COVID-19 patients with significant inflammation measured by elevated C-reactive protein and D-dimer were at a higher risk of acute PE [106]. PE was detected frequently in the periphery than in the central pulmonary arteries [107]. The most frequent site was the segmental, followed by the lobar, central, and subsegmental PE [106]. Acute PE was observed at a greater prevalence in COVID-19 patients with an increased Body mass index (BMI) [106].
A systematic review and meta-analysis on PE and DVT in COVID-19 patients disclosed a higher pooled PE incidence of 24.7% in ICU patients. This percentage is substantially higher than the proportion seen in other viral pneumonia admitted to ICU in the presence or absence of acute respiratory distress syndrome (1.3%–7.5%) [108, 109]. In contrast, it was 10.5% in non-ICU patients (higher than the usual) [107]. Overall the incidence rates of PE and DVT in COVID-19 patients were 16.5% and 14.8% [107]. COVID -19 infection severity and CTPA universal screening correlated with a greater frequency of PE diagnosis. DVT was a concurrent finding in 42.4% of patients with acute PE. An elevated BMI (> 30) correlated substantially with a 2.7 times higher frequency of an acute PE [106]. As observed in a recent study, obese patients with COVID-19 suffer from a more severe disease [110]. A meta-analysis revealed an increased prevalence of venous thromboembolism and acute PE with increasing age in COVID-19 patients [111].
Acute PE is an emergency, and ongoing research will reveal newer biochemical assays and better imaging studies for accurate earlier detection of acute PE in the upcoming few years. SPECT V/Q scan is currently undergoing evaluation at multiple centers where it is being compared to planar V/Q study and CTPA in suspected PE patients for accuracy. Physicians must understand the fallacies of each biochemical test and imaging study for their appropriate utilization in a clinical scenario for the patient’s best outcome. Critical ECG findings and bedside echocardiogram findings should be stressed upon admission and utilized for prognostification. Physicians should be aware that these clinical scores or prediction rules play no role in hospitalized patients and should not be used for decision-making in this particular patient subset.
“No external funds have been utilized in the preparation of this manuscript.”
“We declare no conflict of interest.”
“We thank the editor for allowing us to author this manuscript.
Pulmonary embolism
Computed tomography
United States of America
Medical intensive care unit
Surgical intensive care unit
Deep vein thrombosis
Lower extremity
Pulmonic component of second heart sound
Fourth heart sound
Neutrophil to Lymphocyte ratio
Platelet to Lymphocyte ratio
N-terminal pro Brain natriuretic peptide
Brain natriuretic peptide
Right ventricle
Heart-type fatty acid-binding protein
Arterial blood gas
Negative predictive value
Electrocardiogram
Right bundle branch block
Acute coronary syndrome
Transthoracic echocardiogram
Transesophageal echocardiogram
Tricuspid valve regurgitation
Right ventricle end-diastolic diameter
Tricuspid annular plane systolic excursion
Right ventricle systolic pressure
American College of Emergency physicians
Transthoracic lung ultrasound
Endobronchial ultrasound
Cardiopulmonary ultrasound
Computed tomography pulmonary angiography
Bedside lung ultrasound in emergency
Ventilation / Perfusion
Prospective investigation of pulmonary embolism diagnosis
Prospective Investigative Study of Acute Pulmonary Embolism
Single Photon Emission Computed Tomography
Computed tomography venography
Pulmonary embolism rule-out criteria
Coronavirus disease 2019
Body mass index
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2022",editors:[{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1175",title:"Neuroplasticity",slug:"neuroplasticity",parent:{id:"213",title:"Neurobiology",slug:"life-sciences-neuroscience-neurobiology"},numberOfBooks:3,numberOfSeries:0,numberOfAuthorsAndEditors:70,numberOfWosCitations:36,numberOfCrossrefCitations:40,numberOfDimensionsCitations:88,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"1175",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"6250",title:"The Hippocampus",subtitle:"Plasticity and Functions",isOpenForSubmission:!1,hash:"78f1e57726307f003f39510c175c3102",slug:"the-hippocampus-plasticity-and-functions",bookSignature:"Ales Stuchlik",coverURL:"https://cdn.intechopen.com/books/images_new/6250.jpg",editedByType:"Edited by",editors:[{id:"207908",title:"Dr.",name:"Ales",middleName:null,surname:"Stuchlik",slug:"ales-stuchlik",fullName:"Ales Stuchlik"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6092",title:"Neuroplasticity",subtitle:"Insights of Neural Reorganization",isOpenForSubmission:!1,hash:"1003fc63680b1c04e9135f3dea18a8c3",slug:"neuroplasticity-insights-of-neural-reorganization",bookSignature:"Victor V. Chaban",coverURL:"https://cdn.intechopen.com/books/images_new/6092.jpg",editedByType:"Edited by",editors:[{id:"83427",title:"Prof.",name:"Victor",middleName:null,surname:"Chaban",slug:"victor-chaban",fullName:"Victor Chaban"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5521",title:"Synaptic Plasticity",subtitle:null,isOpenForSubmission:!1,hash:"9eea3c7f926cd466ddd14ab777b663d8",slug:"synaptic-plasticity",bookSignature:"Thomas Heinbockel",coverURL:"https://cdn.intechopen.com/books/images_new/5521.jpg",editedByType:"Edited by",editors:[{id:"70569",title:"Dr.",name:"Thomas",middleName:null,surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:3,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"59437",doi:"10.5772/intechopen.74318",title:"Music and Brain Plasticity: How Sounds Trigger Neurogenerative Adaptations",slug:"music-and-brain-plasticity-how-sounds-trigger-neurogenerative-adaptations",totalDownloads:2157,totalCrossrefCites:6,totalDimensionsCites:16,abstract:"This contribution describes how music can trigger plastic changes in the brain. We elaborate on the concept of neuroplasticity by focussing on three major topics: the ontogenetic scale of musical development, the phenomenon of neuroplasticity as the outcome of interactions with the sounds and a short survey of clinical and therapeutic applications. First, a distinction is made between two scales of description: the larger evolutionary scale (phylogeny) and the scale of individual development (ontogeny). In this sense, listeners are not constrained by a static dispositional machinery, but they can be considered as dynamical systems that are able to adapt themselves in answer to the solicitations of a challenging environment. Second, the neuroplastic changes are considered both from a structural and functional level of adaptation, with a special focus on the recent findings from network science. The neural activity of the medial regions of the brain seems to become more synchronised when listening to music as compared to rest, and these changes become permanent in individuals such as musicians with year-long musical practice. As such, the question is raised as to the clinical and therapeutic applications of music as a trigger for enhancing the functionality of the brain, both in normal and impaired people.",book:{id:"6092",slug:"neuroplasticity-insights-of-neural-reorganization",title:"Neuroplasticity",fullTitle:"Neuroplasticity - Insights of Neural Reorganization"},signatures:"Mark Reybrouck, Peter Vuust and Elvira Brattico",authors:[{id:"196698",title:"Prof.",name:"Mark",middleName:null,surname:"Reybrouck",slug:"mark-reybrouck",fullName:"Mark Reybrouck"},{id:"209976",title:"Prof.",name:"Elvira",middleName:null,surname:"Brattico",slug:"elvira-brattico",fullName:"Elvira Brattico"},{id:"209977",title:"Prof.",name:"Peter",middleName:null,surname:"Vuust",slug:"peter-vuust",fullName:"Peter Vuust"}]},{id:"57827",doi:"10.5772/intechopen.71165",title:"A Role for the Longitudinal Axis of the Hippocampus in Multiscale Representations of Large and Complex Spatial Environments and Mnemonic Hierarchies",slug:"a-role-for-the-longitudinal-axis-of-the-hippocampus-in-multiscale-representations-of-large-and-compl",totalDownloads:1442,totalCrossrefCites:6,totalDimensionsCites:13,abstract:"The hippocampus is involved in spatial navigation and memory in rodents and humans. Anatomically, the hippocampus extends along a longitudinal axis that shows a combination of graded and specific interconnections with neocortical and subcortical brain areas. Functionally, place cells are found all along the longitudinal axis and exhibit gradients of properties including an increasing dorsal-to-ventral place field size. We propose a view of hippocampal function in which fine-dorsal to coarse-ventral overlapping representations collaborate to form a multi-level representation of spatial and episodic memory that is dominant during navigation in large and complex environments or when encoding complex memories. This view is supported by the fact that the effects of ventral hippocampal damage are generally only found in larger laboratory-scale environments, and by the finding that human virtual navigation studies associate ventral hippocampal involvement with increased environmental complexity. Other mechanisms such as the ability of place cells to exhibit multiple fields and their ability to scale their fields with changes in environment size may be utilized when forming large-scale cognitive maps. Coarse-grained ventral representations may overlap with and provide multi-modal global contexts to finer-grained intermediate and dorsal representations, a mechanism that may support mnemonic hierarchies of autobiographical memory in humans.",book:{id:"6250",slug:"the-hippocampus-plasticity-and-functions",title:"The Hippocampus",fullTitle:"The Hippocampus - Plasticity and Functions"},signatures:"Bruce Harland, Marcos Contreras and Jean-Marc Fellous",authors:[{id:"210681",title:"Dr.",name:"Bruce",middleName:null,surname:"Harland",slug:"bruce-harland",fullName:"Bruce Harland"},{id:"210682",title:"Dr.",name:"Marco",middleName:null,surname:"Contreras",slug:"marco-contreras",fullName:"Marco Contreras"},{id:"210683",title:"Prof.",name:"Jean-Marc",middleName:null,surname:"Fellous",slug:"jean-marc-fellous",fullName:"Jean-Marc Fellous"}]},{id:"61465",doi:"10.5772/intechopen.76603",title:"The Importance of Distinguishing Allocentric and Egocentric Search Strategies in Rodent Hippocampal-Dependent Spatial Memory Paradigms: Getting More Out of Your Data",slug:"the-importance-of-distinguishing-allocentric-and-egocentric-search-strategies-in-rodent-hippocampal-",totalDownloads:1471,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"While the brain works as a dynamic network, with no brain region solely responsible for any particular function, it is generally accepted that the hippocampus plays a major role in memory. Spatial memory operates through the hippocampus with communication with the prefrontal and parietal cortices. This chapter will focus on two separate reference frames involved in spatial memory, egocentric and allocentric, and outline the differences of these reference frames and associated search strategies with relevance to behavioural neuroscience. The importance of dissociating these search strategies is put forward, and steps researchers can take to do so are suggested. Neurophysiological and clinical differences between these spatial reference frames are outlined to further support the view that distinguishing them would be beneficial.",book:{id:"6250",slug:"the-hippocampus-plasticity-and-functions",title:"The Hippocampus",fullTitle:"The Hippocampus - Plasticity and Functions"},signatures:"Adrienne M. Grech, Jay Patrick Nakamura and Rachel Anne Hill",authors:[{id:"230389",title:"Dr.",name:"Rachel",middleName:null,surname:"Hill",slug:"rachel-hill",fullName:"Rachel Hill"},{id:"230394",title:"Ms.",name:"Adrienne",middleName:null,surname:"Grech",slug:"adrienne-grech",fullName:"Adrienne Grech"},{id:"230395",title:"Mr.",name:"Jay",middleName:null,surname:"Nakamura",slug:"jay-nakamura",fullName:"Jay Nakamura"}]},{id:"57312",doi:"10.5772/intechopen.70854",title:"The Hippocampus as a Neural Link between Negative Affect and Vulnerability for Psychostimulant Relapse",slug:"the-hippocampus-as-a-neural-link-between-negative-affect-and-vulnerability-for-psychostimulant-relap",totalDownloads:1591,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"Psychostimulant dependence (including cocaine, amphetamine, and methamphetamine) is a chronic relapsing disorder with significant personal, health, and financial burdens. Attempts at abstinence produce a severe and protracted withdrawal syndrome characterized by stress hypersensitivity that can facilitate drug craving, anxiety, and dysphoria. These negative withdrawal symptoms can induce relapse, maintaining the addiction cycle. The hippocampus mediates cognitive, emotional, and endocrine responses to stressors. The ventral hippocampus is in a pivotal position to regulate the mesoaccumbal dopamine reward system, and interacts with serotonergic and glucocorticoid systems that mediate anxiety and stress responsiveness. Psychostimulant actions on the hippocampus induce long-term changes to these systems and impact the process of adult neurogenesis in the hippocampus, which may facilitate drug dependence by altering drug-cue learning and emotional regulation. Multiple studies indicate that psychostimulant-induced hippocampal neuroadaptations heighten hippocampal-mesoaccumbal activity to amplify drug- and drug-cue responses while persistent dysregulation of hippocampal emotional systems potentiate negative affect. Understanding how psychostimulants modulate the hippocampus to alter hippocampal-mesoaccumbal activity—and how hippocampal neurogenesis influences drug-related memories and reward—is important for identifying novel treatment strategies that can ameliorate negative affect and relapse vulnerability in psychostimulant addiction.",book:{id:"6250",slug:"the-hippocampus-plasticity-and-functions",title:"The Hippocampus",fullTitle:"The Hippocampus - Plasticity and Functions"},signatures:"Jeffrey L. Barr, Brenna Bray and Gina L. Forster",authors:[{id:"145620",title:"Dr.",name:"Gina",middleName:null,surname:"Forster",slug:"gina-forster",fullName:"Gina Forster"},{id:"219827",title:"Dr.",name:"Jeffrey",middleName:null,surname:"Barr",slug:"jeffrey-barr",fullName:"Jeffrey Barr"},{id:"219828",title:"BSc.",name:"Brenna",middleName:null,surname:"Bray",slug:"brenna-bray",fullName:"Brenna Bray"}]},{id:"54143",doi:"10.5772/67127",title:"Plasticity of Dendritic Spines. Not Only for Cognitive Processes",slug:"plasticity-of-dendritic-spines-not-only-for-cognitive-processes",totalDownloads:1384,totalCrossrefCites:0,totalDimensionsCites:6,abstract:"Excitatory synaptic transmission is associated with the input of “new” information at synaptic junctions established by dendritic spines. The role that each type of spine plays in the transmission of the synaptic impulses is different. Indeed, there is a close relationship between the shape of spines and the differential processing of the excitatory synaptic information that is relayed to them, influencing in turn the transmission of synaptic information related to several psychoneural processes.",book:{id:"5521",slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Ignacio González-Burgos, Dulce A. Velázquez-Zamora, David\nGonzález-Tapia, Nallely Vázquez-Hernández and Néstor I. Martínez-\nTorres",authors:[{id:"190521",title:"Dr.",name:"Ignacio",middleName:null,surname:"Gonzalez-Burgos",slug:"ignacio-gonzalez-burgos",fullName:"Ignacio Gonzalez-Burgos"},{id:"196267",title:"Dr.",name:"Dulce A",middleName:null,surname:"Velázquez-Zamora",slug:"dulce-a-velazquez-zamora",fullName:"Dulce A Velázquez-Zamora"},{id:"196269",title:"MSc.",name:"David",middleName:null,surname:"González-Tapia",slug:"david-gonzalez-tapia",fullName:"David González-Tapia"},{id:"196270",title:"MSc.",name:"Nallely",middleName:null,surname:"Vázquez-Hernández",slug:"nallely-vazquez-hernandez",fullName:"Nallely Vázquez-Hernández"},{id:"196271",title:"MSc.",name:"Nestor I",middleName:null,surname:"Martínez-Torres",slug:"nestor-i-martinez-torres",fullName:"Nestor I Martínez-Torres"}]}],mostDownloadedChaptersLast30Days:[{id:"58530",title:"Sleep Disorders in Multiple Sclerosis",slug:"sleep-disorders-in-multiple-sclerosis",totalDownloads:1208,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Patients with multiple sclerosis (MS) have multiple causes of poor sleep and potential triggers may relate to MS-related symptoms, co-morbidities and adverse effects from medication. Sleep disorders may occur independently of demographic factors, gender and clinical condition. The real frequency of sleep disturbances in MS and their impact on the patients’ quality of life are unknown. The prevalence of sleep problems in the population with MS ranges between 47 and 62% and is more frequent in women, as well as having a higher risk of mortality. High psychological burden has been associated with poor sleep and with increased risk of co-morbid conditions such as heart disease, obesity, dyslipidemia and diabetes, which may have a profound impact on long-term health. The poor sleeping patients with MS were more likely to report fatigue and sleepiness. Insomnia is present in mood disorders, restless leg syndrome (RLS), pain, nocturia and obstructive sleep apnea (OSA), in patients with MS. All the symptoms are intermixed, and it is not possible to discern the precipitating factor or the perpetuating factor. Clinicians should routinely ask about sleep when forming a comprehensive care plan for patients with MS. Sleep specialty referrals should be considered for management of conditions that require polysomnography (PSG) diagnosis.",book:{id:"6092",slug:"neuroplasticity-insights-of-neural-reorganization",title:"Neuroplasticity",fullTitle:"Neuroplasticity - Insights of Neural Reorganization"},signatures:"Montserrat González Platas and María Yaiza Pérez Martin",authors:[{id:"202099",title:"Dr.",name:"Montserrat",middleName:null,surname:"Gonzalez Platas",slug:"montserrat-gonzalez-platas",fullName:"Montserrat Gonzalez Platas"},{id:"231355",title:"Dr.",name:"Maria Yaiza",middleName:null,surname:"Perez Martín",slug:"maria-yaiza-perez-martin",fullName:"Maria Yaiza Perez Martín"}]},{id:"53927",title:"GABAergic Synapse Dysfunction and Repair in Temporal Lobe Epilepsy",slug:"gabaergic-synapse-dysfunction-and-repair-in-temporal-lobe-epilepsy",totalDownloads:1668,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Severe medial temporal lobe epilepsy (mTLE) is often associated with pharmacoresistant seizures, impaired memory and mood disorders. In the hippocampus, GABAergic inhibitory interneuron dysfunction and other neural circuit abnormalities contribute to hyperexcitability, but the mechanisms are still not well understood. Experimental approaches aimed at correcting deficits in hippocampal circuits in mTLE include attempts to replace GABAergic interneurons through neural stem cell transplantation. Evidence from studies in rodent mTLE models indicates that transplanted GABAergic progenitor cells integrate into the hippocampus, form inhibitory synapses, reduce seizures and improve cognitive deficits. Here, we review current work in this field and describe potential molecular mechanisms underlying successful transplantation.",book:{id:"5521",slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Meghan A. Van Zandt and Janice R. Naegele",authors:[{id:"154904",title:"Prof.",name:"Janice",middleName:null,surname:"Naegele",slug:"janice-naegele",fullName:"Janice Naegele"},{id:"194530",title:"Ph.D. Student",name:"Meghan",middleName:null,surname:"Van Zandt",slug:"meghan-van-zandt",fullName:"Meghan Van Zandt"}]},{id:"54067",title:"Neuroplasticity in Bipolar Disorder: Insights from Neuroimaging",slug:"neuroplasticity-in-bipolar-disorder-insights-from-neuroimaging",totalDownloads:1630,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Background: Advances in neuroimaging techniques have produced evidence about disrupted frontolimbic circuits related to emotional regulation. These neuroimaging studies may suggest impairments in cellular plasticity in bipolar disorder (BD) patients. However, the long-term use of mood stabilizers may restore these dysfunctions by neurotrophic effects",book:{id:"5521",slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Marlos Vasconcelos Rocha, Fabiana Nery, Amanda Galvão-de-\nAlmeida, Lucas de Castro Quarantini and Ângela Miranda-Scippa",authors:[{id:"192139",title:"Ph.D.",name:"Marlos",middleName:"Vasconcelos",surname:"Rocha",slug:"marlos-rocha",fullName:"Marlos Rocha"},{id:"192876",title:"Dr.",name:"Fabiana",middleName:null,surname:"Nery-Fernandes",slug:"fabiana-nery-fernandes",fullName:"Fabiana Nery-Fernandes"},{id:"192877",title:"Prof.",name:"Ângela",middleName:null,surname:"Miranda-Scippa",slug:"angela-miranda-scippa",fullName:"Ângela Miranda-Scippa"},{id:"192878",title:"Prof.",name:"Lucas",middleName:null,surname:"De Castro Quarantini",slug:"lucas-de-castro-quarantini",fullName:"Lucas De Castro Quarantini"},{id:"192879",title:"Dr.",name:"Giovanna",middleName:null,surname:"Ladeia-Rocha",slug:"giovanna-ladeia-rocha",fullName:"Giovanna Ladeia-Rocha"},{id:"192880",title:"Prof.",name:"Amanda",middleName:null,surname:"Galvão-de Almeida",slug:"amanda-galvao-de-almeida",fullName:"Amanda Galvão-de Almeida"}]},{id:"59437",title:"Music and Brain Plasticity: How Sounds Trigger Neurogenerative Adaptations",slug:"music-and-brain-plasticity-how-sounds-trigger-neurogenerative-adaptations",totalDownloads:2155,totalCrossrefCites:6,totalDimensionsCites:16,abstract:"This contribution describes how music can trigger plastic changes in the brain. We elaborate on the concept of neuroplasticity by focussing on three major topics: the ontogenetic scale of musical development, the phenomenon of neuroplasticity as the outcome of interactions with the sounds and a short survey of clinical and therapeutic applications. First, a distinction is made between two scales of description: the larger evolutionary scale (phylogeny) and the scale of individual development (ontogeny). In this sense, listeners are not constrained by a static dispositional machinery, but they can be considered as dynamical systems that are able to adapt themselves in answer to the solicitations of a challenging environment. Second, the neuroplastic changes are considered both from a structural and functional level of adaptation, with a special focus on the recent findings from network science. The neural activity of the medial regions of the brain seems to become more synchronised when listening to music as compared to rest, and these changes become permanent in individuals such as musicians with year-long musical practice. 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