Natural history, growth rates, and treatment of popliteal artery aneurysms.

BACKGROUND: The natural history of a cohort of patients monitored for popliteal artery aneurysms (PAAs) has not been well described. A prevailing uncertainty exists regarding the optimal surveillance strategies and timing of treatment. The primary aim of the present study was to describe the care trajectory of all patients with PAAs identified at two tertiary vascular centers, both in surveillance and eventually treated. The secondary aim was to define the PAA growth rates. METHODS: A retrospective, multicenter cohort study was performed of all patients with PAAs at two vascular centers in two countries (Sweden, 2009-2016; New Zealand, 2009-2017). Data were collected from electronic medical records regarding the comorbidities, treatment, and outcomes and analyzed on a patient- and extremity-specific level. Treatment was indicated at the occurrence of emergent symptoms or considered at a PAA threshold of >2 cm. The PAAs were divided into small (≤15 mm) and large (>15 mm) aneurysms. The mean surveillance follow-up was 5.1 years. RESULTS: Most of the 241 identified patients (397 limbs) with a diagnosis of PAAs had bilateral aneurysms (n = 156). Most patients were treated within the study period (163 of 241; 68%), and one half of the diagnosed extremities with PAA had been treated (54%; 215 of 397). Among those who had undergone elective repair, treatment had usually occurred within 1 year after the diagnosis (66%; 105 of 158). More small PAAs were detected in the group that had required emergent repair compared with elective repair (6 of 57 [11%] vs 12 of 158 [8%]; P < .001). No differences were found in the mean diameters between the elective and emergent groups (30.1 mm vs 32.2 mm; P = .39). Growth was recorded in 110 PAAs and on multivariate analysis was associated with a larger index diameter (odds ratio, 1.138; 95% confidence interval, 1.040-1.246; P = .005) and a concurrent abdominal aortic aneurysm (odds ratio, 2.553; 95% confidence interval, 1.018-6.402; P = .046). CONCLUSIONS: The present cohort of patients represented a true contemporary clinical setting of monitored PAAs and showed that most of these patients will require elective repair, usually within 1 year. The risk of emergent repair is not negligible for patients with smaller diameter PAAs. However, the optimal selection strategy for preventive early repair is still unknown. Future morphologic studies are needed to support the development of individualized surveillance protocols.

ß-Glucan as Trained Immunity-Based Adjuvants for Rabies Vaccines in Dogs.

The mechanisms of trained immunity have been extensively described in vitro and the beneficial effects are starting to be deciphered in in vivo settings. Prototypical compounds inducing trained immunity, such as ß-glucans, act through epigenetic reprogramming and metabolic changes of innate immune cells. The recent advances in this field have opened new areas for the development of Trained immunity-based adjuvants (TIbAs). In this study, we assessed in dogs the potential immune training effects of ß-glucans as well as their capacity to enhance the adaptive immune response of an inactivated rabies vaccine (Rabisin®). Injection of ß-glucan from Euglena gracilis was performed 1 month before vaccination with Rabisin® supplemented or not with the same ß-glucan used as adjuvant. Trained innate immunity parameters were assessed during the first month of the trial. The second phase of the study was focused on the ability of ß-glucan to enhance adaptive immune responses measured by multiple immunological parameters. B and T-cell specific responses were monitored to evaluate the immunogenicity of the rabies vaccine adjuvanted with ß-glucan or not. Our preliminary results support that adjuvantation of Rabisin® vaccine with ß-glucan elicit a higher B-lymphocyte immune response, the prevailing factor of protection against rabies. ß-glucan also tend to stimulate the T cell response as shown by the cytokine secretion profile of PBMCs re-stimulated ex vivo. Our data are providing new insights on the impact of trained immunity on the adaptive immune response to vaccines in dogs. The administration of ß-glucan, 1 month before or simultaneously to Rabisin® vaccination give promising results for the generation of new TIbA candidates and their potential to provide increased immunogenicity of specific vaccines.

ß-Glucan-Induced Trained Immunity in Dogs.

Several observations in the world of comparative immunology in plants, insects, fish and eventually mammals lead to the discovery of trained immunity in the early 2010's. The first demonstrations provided evidence that innate immune cells were capable of developing memory after a first encounter with some pathogens. Trained immunity in mammals was initially described in monocytes with the Bacille Calmette-Guerin vaccine (BCG) or prototypical agonists like ß-glucans. This phenomenon relies on epigenetic and metabolic modifications leading to an enhanced secretion of inflammatory cytokines when the host encounters homologous or heterologous pathogens. The objective of our research was to investigate the trained immunity, well-described in mouse and human, in other species of veterinary importance. For this purpose, we adapted an in vitro model of trained innate immunity in dogs. Blood enriched monocytes were stimulated with ß-glucans and we confirmed that it induced an increased production of pro-inflammatory and anti-microbial compounds in response to bacterial stimuli. These results constitute the first demonstration of trained immunity in dogs and confirm its signatures in other mammalian species, with an implication of cellular mechanisms similar to those described in mice and humans regarding cellular epigenetics and metabolic regulations.

Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations.

Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary stimulus like BCG. The epigenetic changes subsequently regulate cytokine production and cell metabolism and in turn, epigenetic changes are regulated by these effects. Novel -omics technologies, combined with in vitro models for trained immunity and other immunological techniques, identify the biological pathways within innate cells that enable training by BCG. Future research should aim to identify biomarkers for vaccine heterologous effects, such that they can be applied to epidemiological studies. Linking biological mechanisms to the reduction in all-cause mortality observed in epidemiological studies will strengthen the evidence in favor of vaccine NSEs. The universal acceptance of these NSEs would demand a re-evaluation of current vaccination policies, such as the childhood vaccination recommendations by the World Health Organization, in order to produce the maximum impact on childhood mortality.

Anesthetic management of a patient with Edwards syndrome.

The use of suxamethonium in our case was uneventful and despite craniofacial anomalies, airway management was straightforward. This case illustrates that pediatric patients with trisomy 18, presenting with potentially acute life-threatening conditions and requiring emergency major surgery can be managed successfully with a multidisciplinary approach.