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The COVID‐19 pandemic has highlighted the vulnerability of people with diabetes mellitus (DM) to respiratory viral infections. Despite the short history of COVID‐19, various studies have shown that patients with DM are more likely to have increased hospitalisation and mortality rates as compared to patients without. At present, the mechanisms underlying this susceptibility are unclear. However, prior studies show that the course of COVID‐19 disease is linked to the efficacy of the host’s T‐cell responses. Healthy individuals who can elicit a robust T‐cell response are more likely to limit the severity of COVID‐19. Here, we investigate the hypothesis that an impaired T‐cell response in patients with type 2 diabetes mellitus (T2DM) drives the severity of COVID‐19 in this patient population. While there is currently a limited amount of information that specifically addresses T‐cell responses in COVID‐19 patients with T2DM, there is a wealth of evidence from other infectious diseases that T‐cell immunity is impaired in patients with T2DM. The reasons for this are likely multifactorial, including the presence of hyperglycaemia, glycaemic variability and metformin use. This review emphasises the need for further research into T‐cell responses of COVID‐19 patients with T2DM in order to better inform our response to COVID‐19 and future disease outbreaks., The presence of type 2 diabetes mellitus (T2DM) exacerbates COVID‐19. T‐cell responses in COVID‐19 patients play a key role in determining disease outcome. However, T2DM is known to impede T‐cell responses in viral infections. In this review, we discuss the effects of T2DM on diminished T‐cell responses during COVID‐19 and the possible underlying mechanisms.

Intragravidic and perinatal infections, acting through either direct viral effect or immune‐mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up‐to‐date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID‐19 longitudinal studies., Intragravidic and perinatal infections are recognized causes of liability for neurodevelopmental disorders in the progeny. This review aims to discuss the up‐to‐date evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers.

Immunotherapy approaches that target peptide–human leukocyte antigen (pHLA) complexes are becoming highly attractive because of their potential to access virtually all foreign and cellular proteins. For this reason, there has been considerable interest in the development of the natural ligand for pHLA, the T‐cell receptor (TCR), as a soluble drug to target disease‐associated pHLA presented at the cell surface. However, native TCR stability is suboptimal for soluble drug development, and natural TCRs generally have weak affinities for pHLAs, limiting their potential to reach efficacious receptor occupancy levels as soluble drugs. To overcome these limitations and make full use of the TCR as a soluble drug platform, several protein engineering solutions have been applied to TCRs to enhance both their stability and affinity, with a focus on retaining target specificity and selectivity. Here, we review these advances and look to the future for the next generation of soluble TCR‐based therapies that can target monomorphic HLA‐like proteins presenting both peptide and nonpeptide antigens., Native TCR stability and affinity are suboptimal for soluble drug development, limiting their potential as soluble drugs. To overcome these limitations and make full use of the TCR as a soluble drug platform, several protein engineering solutions have been applied to TCRs to enhance both their stability and affinity, with a focus on retaining target specificity and selectivity.

Cellular senescence, a stable cell division arrest caused by severe damage and stress, is a hallmark of aging in humans. Here, we review mechanisms of senescence that are related to mitochondria and their interorganelle communication, and the involvement of proteostasis networks and metabolic control in the senescent phenotype. We also explore possibilities to target these mechanisms as new opportunities for pharmacological interventions with the aim of tissue rejuvenation., Cellular senescence, a stable cell division arrest caused by severe damage and stress, is a hallmark of aging in vertebrates including humans. With progressing age, senescent cells accumulate in a variety of mammalian tissues, where they contribute to tissue aging, identifying cellular senescence as a major target to delay or prevent aging. There is an increasing demand for the discovery of new classes of small molecules that would either avoid or postpone cellular senescence by selectively eliminating senescent cells from the body (i.e., ‘senolytics’) or inactivating/switching damage‐inducing properties of senescent cells (i.e., ‘senostatics/senomorphics’), such as the senescence‐associated secretory phenotype. Whereas compounds with senolytic or senostatic activity have already been described, their efficacy and specificity has not been fully established for clinical use yet. Here, we review mechanisms of senescence that are related to mitochondria and their interorganelle communication, and the involvement of proteostasis networks and metabolic control in the senescent phenotype. These cellular functions are associated with cellular senescence in in vitro and in vivo models but have not been fully exploited for the search of new compounds to counteract senescence yet. Therefore, we explore possibilities to target these mechanisms as new opportunities to selectively eliminate and/or disable senescent cells with the aim of tissue rejuvenation. We assume that this research will provide new compounds from the chemical space which act as mimetics of caloric restriction, modulators of calcium signaling and mitochondrial physiology, or as proteostasis optimizers, bearing the potential to counteract cellular senescence, thereby allowing healthy aging.

Apoptosis, the most extensively studied form of programmed cell death, is essential for organismal homeostasis. Apoptotic cell death has widely been reported as a tumor suppressor mechanism. However, recent studies have shown that apoptosis exerts noncanonical functions and may paradoxically promote tumor growth and metastasis. The hijacking of apoptosis by cancer cells may arise at different levels, either via the interaction of apoptotic cells with their local or distant microenvironment, or through the abnormal pro‐oncogenic roles of the main apoptosis effectors, namely caspases and mitochondria, particularly upon failed apoptosis. In this review, we highlight some of the recently described mechanisms by which apoptosis and these effectors may promote cancer aggressiveness. We believe that a better understanding of the noncanonical roles of apoptosis may be crucial for developing more efficient cancer therapies., Apoptosis exerts noncanonical pro‐oncogenic effects. Firstly, apoptotic cells release various paracrine factors that instruct cancer cells to proliferate, develop drug resistance, or avoid immune surveillance. Secondly, minority MOMP, which is characterized by permeabilization of few mitochondria and nonlethal caspase activation, triggers DNA damage and mutagenesis, and it increases cancer aggressiveness. Thirdly, mitochondria have pro‐oncogenic functions through either their cell‐to‐cell transfer or mitochondrial dynamics.

Elderly patients infected with SARS‐CoV‐2 are at higher risk of developing severe COVID‐19 compared with younger individuals. This outcome could be due to aging‐related alterations in host resistance and disease tolerance mechanisms against pulmonary immunopathology. We review the current knowledge on how aging affects these mechanisms and advocate for more detailed studies on how aging affects viral infection to improve the management of its associated clinical outcome., The ongoing coronavirus disease 2019 (COVID‐19) crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has triggered a large‐scale pandemic that is afflicting millions of individuals in over 200 countries. The clinical spectrum caused by SARS‐CoV‐2 infections can range from asymptomatic infection to mild undifferentiated febrile illness to severe respiratory disease with multiple complications. Elderly patients (aged 60 and above) with comorbidities such as cardiovascular diseases and diabetes mellitus appear to be at highest risk of a severe disease outcome. To protect against pulmonary immunopathology caused by SARS‐CoV‐2 infection, the host primarily depends on two distinct defense strategies: resistance and disease tolerance. Resistance is the ability of the host to suppress and eliminate incoming viruses. By contrast, disease tolerance refers to host responses that promote host health regardless of their impact on viral replication. Disruption of either resistance or disease tolerance mechanisms or both could underpin predisposition to elevated risk of severe disease during viral infection. Aging can disrupt host resistance and disease tolerance by compromising immune functions, weakening of the unfolded protein response, progressive mitochondrial dysfunction, and altering metabolic processes. A comprehensive understanding of the molecular mechanisms underlying declining host defense in elderly individuals could thus pave the way to provide new opportunities and approaches for the treatment of severe COVID‐19.

The Rab family of small GTPases regulates intracellular membrane trafficking by orchestrating the biogenesis, transport, tethering, and fusion of membrane‐bound organelles and vesicles. Like other small GTPases, Rabs cycle between two states, an active (GTP‐loaded) state and an inactive (GDP‐loaded) state, and their cycling is catalyzed by guanine nucleotide exchange factors (GEFs) and GTPase‐activating proteins (GAPs). Because an active form of each Rab localizes on a specific organelle (or vesicle) and recruits various effector proteins to facilitate each step of membrane trafficking, knowing when and where Rabs are activated and what effectors Rabs recruit is crucial to understand their functions. Since the discovery of Rabs, they have been regarded as one of the central hubs for membrane trafficking, and numerous biochemical and genetic studies have revealed the mechanisms of Rab functions in recent years. The results of these studies have included the identification and characterization of novel GEFs, GAPs, and effectors, as well as post‐translational modifications, for example, phosphorylation, of Rabs. Rab functions beyond the simple effector‐recruiting model are also emerging. Furthermore, the recently developed CRISPR/Cas technology has enabled acceleration of knockout analyses in both animals and cultured cells and revealed previously unknown physiological roles of many Rabs. In this review article, we provide the most up‐to‐date and comprehensive lists of GEFs, GAPs, effectors, and knockout phenotypes of mammalian Rabs and discuss recent findings in regard to their regulation and functions., The Rab family of small GTPases regulates intracellular membrane trafficking by localizing on specific organelles (or vesicles) and recruiting various effector proteins to facilitate each step of membrane trafficking. In this review article, we provide the most up‐to‐date and comprehensive lists of guanine nucleotide exchange factors, GTPase‐activating proteins, effectors, and knockout phenotypes of mammalian Rabs and discuss recent findings in regard to their regulation and functions.

Light chain amyloidosis (AL) is a systemic disease in which abnormally proliferating plasma cells secrete large amounts of mutated antibody light chains (LCs) that eventually form fibrils. The fibrils are deposited in various organs, most often in the heart and kidney, and impair their function. The prognosis for patients diagnosed with AL is generally poor. The disease is set apart from other amyloidoses by the huge number of patient-specific mutations in the disease-causing and fibril-forming protein. The molecular mechanisms that drive the aggregation of mutated LCs into fibrils have been enigmatic, which hindered the development of efficient diagnostics and therapies. In this review, we summarize our current knowledge on AL amyloidosis and discuss open issues.

Funder: European Hematology Association; Id: http://dx.doi.org/10.13039/100008594, Funder: La Ligue contre le cancer; Id: http://dx.doi.org/10.13039/501100004099, Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100004440, Funder: Association Laurette Fugain; Id: http://dx.doi.org/10.13039/100007394, Funder: Biotechnology and Biological Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000268, Funder: Assistance Publique ‐ Hôpitaux de Paris; Id: http://dx.doi.org/10.13039/501100002738, Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265, Funder: Institut National Du Cancer; Id: http://dx.doi.org/10.13039/501100006364, It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform approaches to diagnosis and management of immature leukaemias, with a specific focus on T‐lymphoid and myeloid cases. In particular, we consider whether next‐generation analytical tools could provide new perspectives that could improve our understanding of immature blood cancer biology.

Inborn errors of immunity (IEIs) are a group of genetically defined disorders leading to defective immunity. Some IEIs have been linked to mutations of immune receptors or signaling molecules, resulting in defective signaling of respective cascades essential for combating specific pathogens. However, it remains incompletely understood why in selected IEIs, such as X‐linked lymphoproliferative syndrome type 2 (XLP‐2), hypo‐immune response to specific pathogens results in persistent inflammation. Moreover, mechanisms underlying the generation of anticytokine autoantibodies are mostly unknown. Recently, IEIs have been associated with coronavirus disease 2019 (COVID‐19), with a small proportion of patients that contract severe COVID‐19 displaying loss‐of‐function mutations in genes associated with type I interferons (IFNs). Moreover, approximately 10% of patients with severe COVID‐19 possess anti‐type I IFN‐neutralizing autoantibodies. Apart from IEIs that impair immune responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), SARS‐CoV‐2 encodes several proteins that suppress early type I IFN production. One primary consequence of the lack of type I IFNs during early SARS‐CoV‐2 infection is the increased inflammation associated with COVID‐19. In XLP‐2, resolution of inflammation rescued experimental subjects from infection‐induced mortality. Recent studies also indicate that targeting inflammation could alleviate COVID‐19. In this review, we discuss infection‐induced inflammation in IEIs, using XLP‐2 and COVID‐19 as examples. We suggest that resolving inflammation may represent an effective therapeutic approach to these diseases., Inborn error of immunity (IEI) like XLP‐2 is susceptible to infection‐induced inflammation. Autoantibodies to interferons (IFNs), the late onset of immunodeficiency, impair responses to microbes. Immunodeficiency nature of severe coronavirus disease 2019 (COVID‐19) is comprised of IEIs in IFN‐I pathway, autoantibodies to IFN‐I, and suppression of IFN‐I by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The lack of IFN‐I responses leads to uncontrolled SARS‐CoV‐2 replication, excess infection‐induced inflammation that is exemplified by severe COVID‐19 syndromes. ​

Goblet cells are specialized epithelial cells that are essential to the formation of the mucus barriers in the airways and intestines. Armed with an arsenal of defenses, goblet cells can rapidly respond to infection but must balance this response with maintaining homeostasis. Whereas goblet cell defenses against bacterial and parasitic infections have been characterized, we are just beginning to understand their responses to viral infections. Here, we outline what is known about the enteric and respiratory viruses that target goblet cells, the direct and bystander effects caused by viral infection and how viral interactions with the mucus barrier can alter the course of infection. Together, these factors can play a significant role in driving viral pathogenesis and disease outcomes., Goblet cells are tasked with maintaining the mucus barrier at mucosal sites throughout the body. In this review, we examine how both direct and bystander effects caused by enteric and respiratory viral infection can lead to pathogenesis, with emphasis on mucus–virus and host–microbe interactions that can alter infection and disease.

Every cell in vertebrates possesses the machinery to synthesise cholesterol and to metabolise it. The major route of cholesterol metabolism is conversion to bile acids. Bile acids themselves are interesting molecules being ligands to nuclear and G protein‐coupled receptors, but perhaps the intermediates in the bile acid biosynthesis pathways are even more interesting and equally important. Here, we discuss the biological activity of the different intermediates generated in the various bile acid biosynthesis pathways. We put forward the hypothesis that the acidic pathway of bile acid biosynthesis has primary evolved to generate signalling molecules and its utilisation by hepatocytes provides an added bonus of producing bile acids to aid absorption of lipids in the intestine., Have bile acid biosynthesis pathways evolved primarily to generate signalling molecules? and is bile acid formation in the hepatocyte is just a bonus? Intermediates in the conversion of cholesterol to bile acids have important roles in development, immunity, regulation of metabolism and neural homeostasis.

Stromal fibroblasts are central mediators of chronic inflammatory disease. Changes to fibroblast metabolism (including glycolysis, oxidative phosphorylation, pentose phosphate pathway, glutamine metabolism and lactate transport) fuels and underpins the switch in fibroblast phenotype towards an inflammatory‐activated phenotype that drives chronic inflammation. Cancer‐associated fibroblasts drive tumour progression, activated synoviocytes drive joint inflammation, and activated myoblasts drive fibrotic disorders including chronic kidney disease, pulmonary fibrosis, heart disease and liver disease., Mesenchymal stromal fibroblasts have emerged as key mediators of the inflammatory response and drivers of localised inflammation, in part through their interactions with resident and circulating immune cells at inflammatory sites. As such, they have been implicated in a number of chronic inflammatory conditions as well as in tumour progression through modifying the microenvironment. The connection between metabolic changes and altered phenotype of fibroblasts in inflammatory microenvironments has clear implications for our understanding of how chronic inflammation is regulated and for the development of new anti‐inflammatory therapeutics. In this review, we consider the evidence that changes to fibroblast metabolic state underpin chronic inflammation. We examine recent research on fibroblast metabolism in inflammatory microenvironments and consider their involvement in inflammation, providing insight into the role of fibroblasts and metabolism in mediating inflammatory disease progression namely cancer, arthritis and fibrotic disorders including chronic kidney disease, pulmonary fibrosis, heart disease and liver disease.

The anthracycline drug doxorubicin is an effective anticancer drugs with both DNA‐ and chromatin‐damaging activity. While the chromatin‐damaging activity constitutes major anticancer efficacy of doxorubicin, combination with the DNA‐damaging activity plagues the drug with long‐term toxicities such as cardiotoxicity, therapy‐related malignancies and gonadotoxicity. Therefore, developing DNA damage‐free anthracyclines is a promising direction for novel treatment options with limited side effects, which has been shown to be possible., The anthracycline drug doxorubicin is among the most used—and useful—chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy‐related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double‐strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA‐damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure–activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.

This review discusses how the control of proliferation and cell division by cell cycle regulators is also involved in the metabolic adaptive responses when cells need to produce energy. We describe how cell cycle regulators are involved in the control of metabolic pathways, in cell growth and the functionality of organelles including endolysosomes and mitochondria., Adapting to changes in nutrient availability and environmental conditions is a fundamental property of cells. This adaptation requires a multi‐directional coordination between metabolism, growth, and the cell cycle regulators (consisting of the family of cyclin‐dependent kinases (CDKs), their regulatory subunits known as cyclins, CDK inhibitors, the retinoblastoma family members, and the E2F transcription factors). Deciphering the mechanisms accountable for this coordination is crucial for understanding various patho‐physiological processes. While it is well established that metabolism and growth affect cell division, this review will focus on recent observations that demonstrate how cell cycle regulators coordinate metabolism, cell cycle progression, and growth. We will discuss how the cell cycle regulators directly regulate metabolic enzymes and pathways and summarize their involvement in the endolysosomal pathway and in the functions and dynamics of mitochondria.

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism., European Research Council (ERC-2016-StG 715322-EndoMitTalk), and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), Fondo Europeo de Desarrollo Regional (FEDER). GS-H was funded by a FPIUAM grant (Universidad Autonoma de Madrid). MMGH was funded by ERC. EG-R was funded by a Juan de la Cierva grant (IJC2018-036850-I; Universidad Autónoma de Madrid). JO was funded by a Juan de la Cierva grant (FJCI-2017-33855; Universidad Autónoma de Madrid).

Modification of proteins with Met1-linked 'linear' ubiquitin chains has emerged as a key regulatory signal to control inflammatory signalling via the master regulator, the transcription factor nuclear factor κB (NF-κB). While the assembly machinery, the linear ubiquitin chain assembly complex (LUBAC), and receptors for this ubiquitin chain type have been known for years, it was less clear which deubiquitinating enzymes (DUBs) hydrolyse Met1 linkages specifically. In 2013, two labs reported the previously unannotated protein FAM105B/OTULIN to be this missing Met1 linkage-specific DUB. Structural studies have revealed how OTULIN achieves its remarkable specificity, employing a mechanism of ubiquitin-assisted catalysis in which a glutamate residue on the substrate complements the active site of the enzyme. The specificity of OTULIN enables it to regulate global levels of Met1-linked polyubiquitin in cells. This ability led to investigations of NF-κB activation from new angles, and also revealed involvement of Met1-polyubiquitin in Wnt signalling. Interestingly, OTULIN directly interacts with LUBAC, and this interaction is dynamic and can be regulated by OTULIN phosphorylation. This provides a new paradigm for how individual linkage types can be regulated by dedicated enzyme complexes mediating assembly and removal. Here we review what has been learned about OTULIN's mechanism, regulation and function, discuss the open questions in the field, and discuss how DUBs regulate the NF-κB response.

Three-dimensional (3D) guidance for endovascular procedures has developed over the last decade from 3D rotational angiography to the use of dynamic 3D roadmap techniques. The latest development is image merging. This technique combines real-time feedback of fluoroscopy with optimal soft-tissue contrast of previously performed computed tomography (CT) or magnetic resonance angiography. Merging of CT angiography and cone-beam CT/fluoroscopic images is feasible, and preliminary results look promising. Merging will allow us to further reduce radiation exposure, contrast dose, and procedural time, and its main use and benefit will be in complex endovascular interventions.

Rapid response to environmental changes is achieved by uni‐ and multicellular organisms through a series of molecular events, often involving modification of macromolecules, including proteins, nucleic acids and lipids. Amongst these, ADP‐ribosylation is of emerging interest because of its ability to modify different macromolecules in the cells, and its association with many key biological processes, such as DNA‐damage repair, DNA replication, transcription, cell division, signal transduction, stress and infection responses, microbial pathogenicity and aging. In this review, we provide an update on novel pathways and mechanisms regulated by ADP‐ribosylation in organisms coming from all kingdoms of life., ADP‐ribosyltransferases (ARTs) utilise NAD+ as a substrate to modify different molecular targets and control wide variety of processes in organisms of all domains of life.

In the past decade, thoracic endovascular aortic repair (TEVAR) has become the primary treatment option in descending aneurysm and dissection. The clinical outcome of this minimally invasive technique is strictly related to an appropriate patient/stent graft selection, hemodynamic interactions, and operator skills. In this context, a quantitative assessment of the biomechanical stress induced in the aortic wall due to the stent graft may support the planning of the procedure. Different techniques of medical imaging, like computed tomography or magnetic resonance imaging, can be used to evaluate dynamics in the thoracic aorta. Such information can also be combined with dedicated patient-specific computer-based simulations, to provide a further insight into the biomechanical aspects. In clinical practice, computational analysis might show the development of aortic disease, such as the aortic wall segments which experience higher stress in places where rupture and dissection may occur. In aortic dissections, the intimal tear is usually located at the level of the sino-tubular junction and/or at the origin of the left subclavian artery. Besides, computational models may potentially be used preoperatively to predict stent graft behavior, virtually testing the optimal stent graft sizing, deployment, and conformability, in order to provide the best endovascular treatment. The present study reviews the current literature regarding the use of computational tools for TEVAR biomechanics, highlighting their potential clinical applications.

A concise state-of-the-art survey of fiber-reinforced polymer (also known as fiber-reinforced plastic) composites for construction applications in civil engineering is presented. The paper is organized into separate sections on structural shapes, bridge decks, internal reinforcements, externally bonded reinforce ments, and standards and codes. Each section includes a historical review, the current state of the art, and future challenges., the published version in ASCE's Civil Engineering Database(http://cedb.asce.org)

Hypoxia and inflammation have been associated with a number of pathological conditions, in particular inflammatory diseases. While hypoxia is mainly associated with the activation of hypoxia‐inducible factors (HIFs), inflammation activates the family of transcription factor called nuclear factor‐kappa B (NF‐κB). An extensive crosstalk between these two main molecular players involved in hypoxia and inflammation has been demonstrated. This crosstalk includes common activating stimuli, shared regulators and targets. In this review, we discuss the current understanding of the role of NF‐κB and HIF in the context of the immune response. We review the crosstalk between HIF and NF‐κB in the control of the immune response in different immune cell types including macrophages, neutrophils and B and T cells. Furthermore the importance of the molecular crosstalk between HIFs and NF‐κB for a variety of medical conditions will be discussed.

The prevalence of endograft infections (EI) after endovascular abdominal aortic aneurysm repair is below 1%. With the growing number of patients with aortic endografts and the aging population, the number of patients with EI might also increase. The diagnosis is based on an association of clinical symptoms, imaging, and microbial cultures. Angio-computed tomography is currently the gold-standard technique for diagnosis. Low-grade infection sometimes requires nuclear medicine imaging to make a correct diagnosis. There is no good evidence to guide management so far. In the case of active gastrointestinal bleeding, pseudoaneurysm, or extensive perigraft purulence involving adjacent organs, an invasive treatment should always be attempted. In the other cases (the majority), when there is not an immediate danger to the patient's life, a conservative management is started with a proper antimicrobial therapy. Any infectious cavity can be percutaneously drained. Management depends on the patient's condition and a tailored approach should always be offered. In the case of a patient who is young, has a good life expectancy, or in whom there is absence of significant comorbidities, a surgical attempt can be proposed. Surgical techniques favor, in terms of mortality, patency, and reinfection rate, the in situ reconstruction. Choice of technique relies on the center and the operator's experience. Long-term antibiotic therapy is always required in all cases, with close monitoring of the C-reactive protein.

According to international guidelines, stable patients with uncomplicated Type B aortic dissection (TBAD) should receive optimal medical treatment. Despite adequate antihypertensive therapy, the long-term prognosis of these patients is characterized by a significant aortic aneurysm formation in 25-30% within four years, and survival rates from 50 to 80% at five years and 30 to 60% at 10 years. In a prospective randomized trial, preemptive thoracic endovascular aortic repair (TEVAR) in patients with chronic uncomplicated TBAD was associated with an excess early mortality (due to periprocedural hazards), but the procedure showed its benefit in prevention of aortic-specific mortality at five years of follow-up. However, preemptive TEVAR may not be the treatment of choice in all patients with uncomplicated TBAD because of the inherent periprocedural complications like stroke, paraparesis, and death, as well as stent graft-induced complications (i.e., retrograde dissection or endoleaks). Thus, the TEVAR-related deaths and complications (especially paraplegia and stroke) raise concerns that moderate the better survival with TEVAR at five years. By timely identification of those patients prone for developing complications, early intervention, preferably in the subacute or early chronic phase, may improve the overall long-term outcome for these patients. Therefore, early detectable and reliable prognostic factors for adverse events are essential to stratify patients who can be treated medically and those who will benefit from rigorous follow-up and, in the long-term, from timely, or even prophylactic, TEVAR. Several studies have identified prognostic factors in TBAD such as aortic diameter, partial false lumen thrombosis, false lumen thickness, and location of the primary entry tear. Combining these clinical and radiological predictors may be essential to implement a patient-specific approach designed to intervene only in those patients who are at high risk of developing complications to improve the long-term outcomes of patients with uncomplicated Type B aortic dissection.

There are many questions that remain unanswered in the understanding of the natural history of thoracic aortic aneurysm (TAA). This review will critically appraise the current published evidence on the natural history of TAA in nonoperated patients and their present rates of survival.

Since 1994, when a small 70-patient study seemed to demonstrate that β-blocker treatment could help prevent aortic aneurysms in patients with Marfan syndrome, β-adrenergic-blocking drugs have been increasingly believed to reduce the progression of aortic aneurysms in the general population with aortic disease. This literature review examines the scientific evidence of this treatment and questions whether β-blocker treatment for aortic aneurysms should continue to be uniformly recommended. Five separate clinical trials studying the effects of β-blockade therapy in patients with Marfan syndrome are analyzed, in addition to four other clinical trials studying the effects of β-blockade therapy in patients without Marfan syndrome. The analysis suggests that the scientific evidence for β-blocker treatment is unconvincing, because β-blockade therapy fails to consistently reduce aortic aneurysm growth in patients with or without Marfan syndrome. It is alarmingly clear that prospective, multicenter clinical trials are greatly needed to test the efficacy of this now conventional therapy in a more robust scientific fashion.