Abdominal aortic aneurysm (AAA) is a degenerative vascular pathology resulting in significant morbidity and mortality in older adults due to rupture and sudden death. Despite 150,000 new cases and nearly 15,000 deaths annually, the only approved treatment for AAA is surgical or endovascular intervention when the risk for aortic rupture is increased. The goal of the scientific community is to develop novel pharmaceutical treatment strategies to reduce the need for surgical intervention. As most clinically-relevant AAAs contain a complex structure of fibrin, inflammatory cells, platelets, and red blood cells in the aneurysmal sac known as an intraluminal thrombus (ILT), antithrombotic therapies have emerged as potential pharmaceutical agents for the treatment of AAA progression. However, the efficacy of these treatments has not been shown, and the effects of shrinking the ILT may be as detrimental as they are beneficial. This review discusses the prospect of anticoagulant and antiplatelet (termed collectively as antithrombotic) therapies in AAA. Herein, we discuss the role of the coagulation cascade and platelet activation in human and animal models of AAA, the composition of ILT in AAA, a possible role of the ILT in aneurysm stabilization, and the implications of antithrombotic drugs in AAA treatment.

Abdominal aortic aneurysm (AAA) is associated with high morbidity and mortality and is an established cause of unbalanced hemostasis. A number of hemostatic biomarkers have been associated with AAA; however, the utility of hemostatic biomarkers in AAA diagnosis and prognosis is unclear. The aim of the present study was to characterize the potential prognostic value of D-dimer and markers of altered hemostasis in a large cohort of patients with AAAs characterized by either fast or slow aneurysm growth (frequency matched for baseline diameter) and subaneurysmal dilations. We measured plasma concentrations of thrombin-antithrombin (TAT) complex, platelet factor 4 (PF4), and D-dimer in 352 patients with either fast-growing AAAs (>2 mm/y), slow-growing AAAs (<2 mm/y), subaneurysmal aortic dilations, or nonaneurysmal aortas. Plasma D-dimer and TAT were significantly elevated in both AAA and subaneurysmal dilation patients compared with controls. Individuals with D-dimer levels ≥500 ng/mL had 3.09 times the odds of subaneurysms, 6.23 times the odds of slow-growing AAAs, and 7.19 times the odds of fast-growing AAAs than individuals with D-dimer level <500 ng/mL. However, no differences in D-dimer concentration were noted between fast- and slow-growing aneurysms. Plasma D-dimer and TAT were strong independent predictors of AAA growth rate with multivariate analysis revealing a 500-ng/mL increase in D-dimer or 1-µg/mL increase in TAT led to additional 0.21-mm and 0.24-mm changes in aortic diameter per year, respectively. Rising levels of plasma TAT, in addition to D-dimer, may predict disease progression and aneurysm growth in patients with AAA or subaneurysmal dilation.

Aims Examine and evaluate the overall effectiveness of age gates preventing access of underage users to alcohol websites. Methods Assess the characteristics of digital age gates among the top 25 alcohol brands among American adolescents, including type of age gate employed and resulting actions of repeated access requests indicating the user was under the legal drinking age. Results All official alcohol brand websites examined included an age gate, requiring either entering one’s date of birth (DOB, 91%) or clicking a yes/no box indicating they were of legal drinking age (9%). Only one out of every five alcohol websites blocked futures attempts to gain access after entering a response indicating the user was under the legal drinking age. Users were allowed indefinite attempts to enter a DOB that was of legal drinking age, with the majority of websites subsequently granting access even after multiple underage entries. Conclusions Alcohol website visitors with minimal arithmetic abilities, such as very young youth, are able to employ ‘trial and error’ to eventually enter an acceptable legal drinking DOB and gain access. Alcohol brand age gates are weak, at best, and likely an inconsequential barrier that someone with limited math abilities can easily overcome.

The activated form of coagulation factor XIII (FXIII-A2B2), FXIII-A*, is a hemostatic enzyme essential for inhibiting fibrinolysis by irreversibly crosslinking fibrin and antifibrinolytic proteins. Despite its importance, there are no modulatory therapeutics. Guided by the observation that humans deficient in FXIII-B have reduced FXIII-A without severe bleeding, we hypothesized that a suitable small interfering RNA (siRNA) targeting hepatic FXIII-B could safely decrease FXIII-A. Here we show that knockdown of FXIII-B with siRNA in mice and rabbits using lipid nanoparticles resulted in a sustained and controlled decrease in FXIII-A. The concentration of FXIII-A in plasma was reduced by 90% for weeks after a single injection and for more than 5 months with repeated injections, whereas the concentration of FXIII-A in platelets was unchanged. Ex vivo, crosslinking of α2-antiplasmin and fibrin was impaired and fibrinolysis was enhanced. In vivo, reperfusion of carotid artery thrombotic occlusion was also enhanced. Re-bleeding events were increased after challenge, but blood loss was not significantly increased. This approach, which mimics congenital FXIII-B deficiency, provides a potential pharmacologic and experimental tool to modulate FXIII-A2B2 activity.

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Background: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. Methods: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor–deficient ( Ldlr −/− ) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 ( Fmo3 −/− ). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. Results: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3 −/− mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells–augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK. Conclusions: These results define a role for gut microbiota–generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress–related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.

Fuel poverty − the inability to afford adequate warmth in the home − is a widespread problem across the UK. Cold, damp homes are detrimental to human health and contribute to thousands of 'excess winter deaths' every year. This article analyses fuel poverty from a human rights perspective -asking whether it engages human rights protections. It first discusses the definition, scale and health impacts of the problem. Second, it explores the relationship between fuel poverty and the rights contained within the European Convention on Human Rights, the International Covenant on Economic, Social and Cultural Rights and the European Social Charter. It concludes that fuel poverty readily engages rights to adequate housing, food and health and certain civil and political rights in extreme circumstances. It discusses the legal implications of these findings for fuel poverty policy, arguing for a 'human rights approach' to tackling the problem. These conclusions focus on the particularly drastic fuel poverty situation in the UK, but can also be applied globally to the various nations where citizens suffer similar problems and extend to the wider debate on the relationship between poverty and human rights.

One of the biggest issues facing the global agriculture industry is the use of genetically modified organisms (GMOs) in crops and food products. This study compares financial performance of major GMO food companies to other industries. Findings indicate that GMO companies had an average higher return on equity but also a higher level of risk. In addition, the study presents positive and negative perspectives toward GMO foods, along with a discussion of the risks and opportunities. Agricultural studies indicate that applying GMO technology is likely the most effective way to feed many of the world's hungry. In addition, research supports the safety and nutritional benefits of GMO food products. However, concerns expressed by GMO opponents have been effective in limiting GMO acceptance by the public. Research indicates that the H. M. Martin et al. inconsistency between negative public opinion and positive scientific evidence supporting GMO crops is at least partly the result of misrepresentations about GMOs. The ultimate acceptance or rejection of GMO foods will greatly affect food producers, distributors, retailers, and consumers.