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Entities of physical presence have always been susceptible to attacks. Entities of online presence are more prone to cyberattacks, as the lack of local boundaries permits anyone from anywhere in the world to launch a potentially successful attack. People aim to protect their physical and virtual assets daily: Locking doors and cars, setting up alarms and protecting passwords and credit card numbers are just a few examples. History has proven, though, that any defense system can be compromised. Defenders and attackers have delved into continuous action and counteraction: The more intelligent the defense strategy gets, the more sophisticated the attacker becomes, and the defense needs to adapt again. Game Theory provides us with the mathematical tools and concepts to capture these strategic interactions between players and their different and often antagonistic interests. Such a concept is a Nash equilibrium: a set of strategies that dictates what the players should do, such that the players have no incentive to deviate. We model the strategic interactions between a strategic adversary and a classifier using Game Theory. Our analysis leads to Nash equilibria in randomized strategies, increasing the difficulty for the attacker to reconstruct the classification rule. We give a polynomial time algorithm to compute the Nash equilibrium strategies of the players. Our setting, albeit simple, gives interesting insights that could be beneficial in practical settings: We quantify the impact of the various parameters like cost from detection, false alarms and statistics about the normal traffic on the equilibrium strategies and payoffs. We show that if the classification is based on several features, the defender should apply a threshold on the attacker's reward. This is in contrast with known algorithms such as logistic regression which have a predefined shape of the boundary independently of the attacker's goal. In view of the recent security breaches, like Anthem, Target and Home Depot, we are motivated to study a class of games in which there are multiple defenders (companies) that compete to acquire legitimate users in the presence of malicious traffic. To this purpose we analyze the economic incentives for ad networks to fight click fraud in advertising markets. By click fraud, we define the act of clicking an ad without an interest to see the ad or buy the advertised product. When such clicks are counted as "valid" by the ad network, the advertiser pays for a useless click, and the publisher (webpage at which the ad was displayed) is rewarded for generating it. Thus there is an incentive for fraudulent publishers to inflate click numbers. Ad networks have an incentive to classify fraudulent clicksin order to deliver a more valuable service to advertisers. On the other hand, ad networks do receive revenue for fraudulent clicks, which creates an incentive in the opposite direction to fight fraud less.We develop a model to capture the incentives of two competing ad networks to fight click fraud, under different assumptions about the bidding process of advertisers. Our equilibrium results show that ad networks are highly incentivized in combating click fraud. We explore the investment strategies of ad networks to improve their classification algorithms and investigate when ad networks over or under invest compared to social optimum.

Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1−/− explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.

Vascular dysfunction contributes to the pro-oncogenic tumor microenvironment and impedes the delivery of therapeutics. Normalizing of the tumor vasculature has therefore become a potential therapeutic objective. We previously reported that the secreted glycoprotein, leucine-rich α-2-glycoprotein 1 (LRG1), contributes to the formation of pathogenic neovascularization. Here we show that in mouse models of cancer, Lrg1 is induced in tumor endothelial cells. We demonstrate that the expression of LRG1 impacts on tumor progression as Lrg1 deletion or treatment with a LRG1 function-blocking antibody inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function resulting in significantly enhanced efficacy of cisplatin chemotherapy, adoptive T-cell therapy and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent (cold) to immune active (hot). LRG1 therefore drives vascular abnormalization and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.

Chronic kidney disease (CKD) related cardiovascular disease (CVD) is characterized by vascular remodelling with well-established structural and functional changes in the vascular wall such as arterial stiffness, matrix deposition, and calcification. These phenotypic changes resemble pathology seen in ageing, and are likely to be mediated by sustained alterations in gene expression, which may be caused by epigenetic changes such as tissue-specific DNA methylation. We aimed to investigate tissue specific changes in DNA methylation that occur in CKD-related CVD. Genome-wide DNA methylation changes were examined in bisulphite converted genomic DNA isolated from the vascular media of CKD and healthy arteries. Methylation-specific PCR was used to validate the array data, and the association between DNA methylation and gene and protein expression was examined. The DNA methylation age was compared to the chronological age in both cases and controls. Three hundred and nineteen differentially methylated regions (DMR) were identified spread across the genome. Pathway analysis revealed that DMRs associated with genes were involved in embryonic and vascular development, and signalling pathways such as TGFβ and FGF. Expression of top differentially methylated gene HOXA5 showed a significant negative correlation with DNA methylation. Interestingly, DNA methylation age and chronological age were highly correlated, but there was no evidence of accelerated age-related DNA methylation in the arteries of CKD patients. In conclusion, we demonstrated that differential DNA methylation in the arterial tissue of CKD patients represents a potential mediator of arterial pathology and may be used to uncover novel pathways in the genesis of CKD-associated complications.

BackgroundAnterior cricoid split is performed for grade 2 and 3 subglottic stenosis, which can be a cause of extubation failure. It can be performed endoscopically or as an open procedure. This paper describes a case series of endoscopic cricoid split procedures performed using a bespoke sickle knife.MethodNine patients (six pre-term infants) underwent endoscopic cricoid split in a tertiary referral paediatric unit between August 2012 and March 2015.ResultsSix patients (67 per cent; four pre-term and two term infants) were on oxygen pre-operatively. Mean age at operation was 30 weeks (range, 11–104 weeks). Mean number of days’ intubation was 5.6 days (range, 4–9 days). All five patients intubated pre-operatively were extubated. Seven patients required repeat dilatations. One patient required tracheostomy.ConclusionThe extubation rates for endoscopic cricoid split are comparable to the open procedure. It is a safe and efficient method for managing subglottic stenosis, whether acquired or congenital. The main advantage is the shorter operative time, in addition to the avoidance of an external scar and drain.

Attack detection is usually approached as a classification problem. However, standard classification tools often perform poorly, because an adaptive attacker can shape his attacks in response to the algorithm. This has led to the recent interest in developing methods for adversarial classification , but to the best of our knowledge, there have been a very few prior studies that take into account the attacker’s tradeoff between adapting to the classifier being used against him with his desire to maintain the efficacy of his attack. Including this effect is a key to derive solutions that perform well in practice. In this investigation, we model the interaction as a game between a defender who chooses a classifier to distinguish between attacks and normal behavior based on a set of observed features and an attacker who chooses his attack features (class 1 data). Normal behavior (class 0 data) is random and exogenous. The attacker’s objective balances the benefit from attacks and the cost of being detected while the defender’s objective balances the benefit of a correct attack detection and the cost of false alarm. We provide an efficient algorithm to compute all Nash equilibria and a compact characterization of the possible forms of a Nash equilibrium that reveals intuitive messages on how to perform classification in the presence of an attacker. We also explore qualitatively and quantitatively the impact of the non-attacker and underlying parameters on the equilibrium strategies.

Summary Background A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility. Methods Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated. Findings In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active. Conclusions LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics. Funding Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366).

Surfer's exostoses are more commonly seen in adults who frequently participate in aquatic activities with repeated exposed to cold water and wind. However, this entity has not been previously reported in the pediatric population. Most patients can be managed conservatively, particularly considering that surgical removal of external auditory canal exostosis can be challenging. Keywords: Ear, Otorhinolaryngology, Pediatric otorhinolaryngology, Exostosis

Although the use of checkpoint inhibitors and adoptive T cell therapy have been reported in multiple cancers resulting in a plethora of clinical trials, the efficacy of these therapeutic strategies is often limited by the presence of impaired vasculature in the tumour mass. Indeed, in solid tumors, blood vessels are dysfunctional, leaky and poorly perfused, and thwart not only the efficacy of systemically derived drugs but also the extravasation of T cells, promoting an immunosuppressive microenvironment. Leucine-rich alpha-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that is associated with pathogenic neovascularization, autoimmune diseases, chronic inflammation, and is significantly up-regulated in many solid cancers. We have observed that treatment with a LRG1 function-blocking antibody (15C4) significantly limits growth of solid tumors inducing vessel normalization and functionality. In the present study, we aim to investigate if LRG1 blockade enhances an immunostimulatory milieu, making tumors more responsive to current immunotherapies. Murine melanoma cells harbouring the internal influenza nucleoprotein antigen, NP68, were grafted subcutaneously before antigen-specific F5B6 CD8+ T cells were also transferred. Interestingly, the combination with 15C4 promoted a greater reduction in tumor growth rate. Moreover, not only was the number of donor CD8+ T cells significantly higher when delivered with 15C4, but also the total number of CD3+ T cells was increased following combination therapy, suggesting a more robust host-derived lymphocyte trafficking. As blocking LRG1 normalizes the tumor vasculature and enhances T cell extravasation, we then evaluated whether 15C4 could improve delivery and efficacy of an anti-PD1 checkpoint inhibitor. As monotherapies, both 15C4 and anti-PD1 antibodies induced a marked reduction in tumor volume but when the two were combined, a significant additive effect was also observed. Histological analysis revealed that the combination therapy was associated with a significantly higher number of activated CD8+ T cells, together with enhanced expression of Granzyme B. Current studies are investigating whether the observed boost in cytotoxic T cell density and functionality is a direct consequence of vessel normalization or whether LRG1 blockade is able to modulate the tumour immune microenvironment at different levels: for example, FACS analysis of tumour-infiltrating leukocytes revealed a reduction in the percentage of regulatory T cells after dual therapy, while histological analysis suggested an increase in the number of M1 macrophages. These data show that LRG1 blockade orchestrates a shift in the tumour microenvironment from being immune silent to immune active and, therefore, might represent a novel tool to enhance the efficacy of cancer therapies. Citation Format: Carlotta Camilli, Camilla Pilotti, Marie N. O'Connor, David Kallenberg, Markella Alatsatianos, Angharad H. Watson, Julia Ohme, Athina Dritsoula, Ann Ager, Stephen E. Moss, John Greenwood. Lrg1 blockade modulates the tumor immune microenvironment and improves the efficacy of cancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 391.

Objective: NKX2-5 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down-regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX2-5 expression in diseased vessels, such as systemic sclerosis (scleroderma; SSc)–associated pulmonary hypertension (PH), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications. Methods: We explored NKX2-5 expression in biopsy samples from patients with SSc-associated PH and in pulmonary artery smooth muscle cells (PASMCs) from patients with scleroderma. Disease-associated putative functional single-nucleotide polymorphisms (SNPs) at the NKX2-5 locus were cloned and studied in reporter gene assays. SNP function was further examined through protein–DNA binding assays, chromatin immunoprecipitation assays, and RNA silencing analyses. Results: Increased NKX2-5 expression in biopsy samples from patients with SSc-associated PH was localized to remodeled vessels and PASMCs. Meta-analysis of 2 independent scleroderma cohorts revealed an association of rs3131917 with scleroderma (P = 0.029). We demonstrated that disease-associated SNPs are located in a novel functional enhancer, which increases NKX2-5 transcriptional activity through the binding of GATA-6, c-Jun, and myocyte-specific enhancer factor 2C. We also characterized an activator/coactivator transcription-enhancer factor domain 1 (TEAD1)/Yes-associated protein 1 (YAP1) complex, which was bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating the transcription of NKX2-5. Conclusion: NKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in PASMCs through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX2-5 activation in cardiovascular disease characterized by vascular remodeling.

Importance There are two clinically significant congenital anomalies of the epiglottis, aplasia and hypoplasia. Early mortality in aplasia is significantly higher than in hypoplasia. Early aggressive intervention may improve outcomes. An approach to diagnosis, treatment and outcomes is discussed. Methods A case of congenital aplasia of the epiglottis and a review of the literature of all the cases previously described is presented. Observations A male newborn underwent microlaryngotracheobronchoscopy (MLTB) due to stridor and difficulty in establishing oral feeds and was diagnosed with congenital aplasia of the epiglottis. He has not required tracheostomy and at 11 months of follow-up is gastrostomy fed and thriving. 9 cases of aplasia and 19 cases of hypoplasia have been described previously. The difference between aplasia and hypoplasia is established based on the clinical appearance at endoscopic examination. Conclusions and relevance Congenital aplasia and hypoplasia of the epiglottis are rare congenital laryngeal anomalies and the majority are associated with a syndrome. Early diagnosis and management in the form of fundoplication/gastrostomy and tracheotomy when required may improve outcomes.

NKX2-5 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down-regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX2-5 expression in diseased vessels, such as systemic sclerosis (scleroderma; SSc)-associated pulmonary hypertension (PH), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications.We explored NKX2-5 expression in biopsy samples from patients with SSc-associated PH and in pulmonary artery smooth muscle cells (PASMCs) from patients with scleroderma. Disease-associated putative functional single-nucleotide polymorphisms (SNPs) at the NKX2-5 locus were cloned and studied in reporter gene assays. SNP function was further examined through protein-DNA binding assays, chromatin immunoprecipitation assays, and RNA silencing analyses.Increased NKX2-5 expression in biopsy samples from patients with SSc-associated PH was localized to remodeled vessels and PASMCs. Meta-analysis of 2 independent scleroderma cohorts revealed an association of rs3131917 with scleroderma (P = 0.029). We demonstrated that disease-associated SNPs are located in a novel functional enhancer, which increases NKX2-5 transcriptional activity through the binding of GATA-6, c-Jun, and myocyte-specific enhancer factor 2C. We also characterized an activator/coactivator transcription-enhancer factor domain 1 (TEAD1)/Yes-associated protein 1 (YAP1) complex, which was bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating the transcription of NKX2-5.NKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in PASMCs through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX2-5 activation in cardiovascular disease characterized by vascular remodeling.

Ad networks use revenue sharing and effective filtering of fraudulent clicks to attract publishers. We develop a simple Hotelling competition-based game-theoretic model to study the effect of competition along these dimensions. We compute the Nash equilibrium strategy for two ad networks that compete for publishers. We then investigate how the preferences of the publishers and the quality of the ad networks affect the market share and the strategies chosen at equilibrium.

We report the unusual case of a 3-year-old child with a Mongolian blue spot present both around the auricle externally and on the tympanic membrane itself.

We consider a game in which a strategic defender classifies an intruder as spy or spammer. The classification is based on the number of file server and mail server attacks observed during a fixed window. The spammer naively attacks (with a known distribution) his main target: the mail server. The spy strategically selects the number of attacks on his main target: the file server. The defender strategically selects his classification policy: a threshold on the number of file server attacks. We model the interaction of the two players (spy and defender) as a nonzero-sum game: The defender needs to balance missed detections and false alarms in his objective function, while the spy has a tradeoff between attacking the file server more aggressively and increasing the chances of getting caught. We give a characterization of the Nash equilibria in mixed strategies, and demonstrate how the Nash equilibria can be computed in polynomial time. Our characterization gives interesting and non-intuitive insights on the players' strategies at equilibrium: The defender uniformly randomizes between a set of thresholds that includes very large values. The strategy of the spy is a truncated version of the spammer's distribution. We present numerical simulations that validate and illustrate our theoretical results.

The genetic disorder primary ciliary dyskinesia (PCD) arises from dysmotility of cilia in the respiratory tract, brain ventricles, oviduct and the embryonic node. Patients have chronic obstructive pulmonary disease, reduced fertility and situs abnormalities. PCD is genetically heterogeneous with 12 genes causing ~40% of all cases, two encoding proteins (KTU, LRRC50) involved in cytosolic axonemal dynein co-assembly. We have identified mutations in the C19ORF51 gene located within a previously mapped PCD locus. C19ORF51 encodes a protein orthologous to PF22, a Chlamydomonas protein involved in the cytoplasmic assembly of outer dynein arms preceeding their import into the axoneme. Chlamydomonas pf22 cells display a disturbance in their cytoplasm of dynein heavy chain stabilityand the co-assembly of heavy with intermediate chains, both essential for dynein arm assembly. PF22 appears to act downstream of KTU and LRRC50 in the dynein preassembly pathway. PF22 knockdown in zebrafish causes a loss of dynein arms, cilia dysmotility, and a typical ciliopathy phenotype with axis curvature, pronephric cysts, hydrocephalus and situs inversus. We propose the existance of a conserved multi-step pathway for formation of assembly-competent dynein complexes, and that PF22 (now renamed DNAAF3, “dynein axonemal assembly factor 3”) mutations cause PCD with situs inversus due to deficient cytoplasmic dynein assembly.

We investigate the problem of classifying an intruder of two different types (spy or spammer). The classification is based on the number of file server and mail server attacks a network defender observes during a fixed window. The spammer naively attacks (with a known distribution) his main target: the mail server. The spy strategically selects the number of attacks on his main target: the file server. The defender strategically selects his classification policy: a threshold on the number of file server attacks. We first develop parameterized families of payoff functions for both players and analyze the Nash equilibria of the noncooperative nonzero-sum game. We analyze the strategic interactions of the two players and the tradeoffs each one of them faces: The defender chooses a classification threshold that balances the cost of missed detections and false alarms while the spy seeks to hit the file server as much as possible while still evading detection. We give a characterization of the Nash equilibria in mixed strategies, and demonstrate how the Nash equilibria can be computed in polynomial time. We give two examples of the general model, one that involves forensics on the side of the defender and one that does not. Finally, we evaluate how investments in forensics and data logging could improve the Nash equilibrium payoff of the defender.

Primary ciliary dyskinesia most often arises from loss of the dynein motors that power ciliary beating. Here we show that DNAAF3 (also known as PF22), a previously uncharacterized protein, is essential for the preassembly of dyneins into complexes before their transport into cilia. We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms. Knockdown of dnaaf3 in zebrafish likewise disrupts dynein arm assembly and ciliary motility, causing primary ciliary dyskinesia phenotypes that include hydrocephalus and laterality malformations. Chlamydomonas reinhardtii PF22 is exclusively cytoplasmic, and a PF22-null mutant cannot assemble any outer and some inner dynein arms. Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway. These results support the existence of a conserved, multistep pathway for the cytoplasmic formation of assembly competent ciliary dynein complexes.