Monocyte Trajectories Endotypes Are Associated With Worsening in Septic Patients

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The immune system plays a key role in sepsis onset and remains dysregulated over time in a heterogeneous manner. Here, we decipher the heterogeneity of the first week evolution of the monocyte HLA-DR (mHLA-DR) surface protein expression in septic patients, a key molecule for adaptive immunity onset. We found and verified four distinctive trajectories endotypes in a discovery (n = 276) and a verification cohort (n = 102). We highlight that 59% of septic patients exhibit low or decreasing mHLA-DR expression while in others mHLA-DR expression increased. This study depicts the first week behavior of mHLA-DR over time after sepsis onset and shows that initial and third day mHLA-DR expression measurements is sufficient for an early risk stratification of sepsis patients. These patients might benefit from immunomodulatory treatment to improve outcomes. Going further, our study introduces a way of deciphering heterogeneity of immune system after sepsis onset which is a first step to reach a more comprehensive landscape of sepsis.

Pathogen-Associated Molecular Patterns: The Synthesis of Heptose Phosphates and Derivatives

Lipopolysaccharide biosynthesis metabolites, such as d-glycero-β-d-manno-heptopyranosyl 1,7-diphosphate, d-glycero-β-d-manno-heptopyranosyl phosphate, and adenosine 5′-(l-glycero-β-d-manno-heptopyranosyl)diphosphate, have been found to activate NF-κB via alpha-kinase 1 and TRAF-interacting protein with forkhead associated domain. This axis has been determined as a novel pathway of innate immunity yet to be targeted for immunomodulatory treatment approaches. Key in understanding this new axis has been the ability to synthesize these metabolites. The design of synthetic analogues and probes have also been published not only to design new drugs, but also to gain insight into the mechanism of action for these compounds. The focus of the present review is the synthesis of heptose phosphate metabolites­ as well as synthetic analogues and probes.1 Introduction2 Synthesis of d-glycero-d-manno-Heptose2.1 Using d-Mannose as Starting Material2.2 Using d-Ribose as Starting Material2.3 Using 2,2-Dimethyl-1,3-dioxan-5-one as Starting Material3 Synthesis of l-glycero-d-manno-Heptose3.1 Using d-Mannose as Starting Material3.2 Using 2,2-Dimethyl-1,3-dioxan-5-one as Starting Material3.3 Using l-Lyxose as Starting Material4 Synthesis of Heptose Phosphates4.1 Synthesis of d-glycero-β-d-manno-Heptose 1,7-Diphosphate4.2 Synthesis of Heptose Phosphate Derivatives4.2.1 Development of Scaffolds for Conjugation4.2.2 Development of Heptose Phosphates Derivatives for Cell Intake and Metabolic Stability5 Conclusion and Outlook

Immunomodulatory treatment and surgical management of idiopathic uveitis and juvenile idiopathic arthritis-associated uveitis in children: a French survey practice

Background Surgeries for idiopathic uveitis and juvenile idiopathic arthritis-associated uveitis in children are complex because of the high risk of inflammatory postoperative complications. There is no consensus about treatment adaptation during the perioperative period. The objectives of this study are to report the therapeutic changes made in France and to determine whether maintaining or stopping immunosuppressive therapies is associated with an increased risk of surgical site infection or an increased risk of uveitis or arthritis flare-up. Methods We conducted a retrospective cohort study between January 1, 2006 and December 31, 2018 in six large University Hospitals in France. Inclusion criteria were chronic idiopathic uveitis or chronic uveitis associated with juvenile idiopathic arthritis under immunosuppressive therapies at the time of the surgical procedure, operated before the age of 16. Data on perioperative treatments, inflammatory relapses and post-operative infections were collected. Results A total of 76 surgeries (42% cataract surgeries, 30% glaucoma surgeries and 16% posterior capsule opacification surgeries) were performed on 37 children. Adaptation protocols were different in the six hospitals. Immunosuppressive therapies were discontinued in five cases (7%) before surgery. All the children in the discontinuation group had an inflammatory relapse within 3 months after surgery compared to only 25% in the other group. There were no postoperative infections. Conclusions The results of this study show varying practices between centres. The benefit-risk balance seems to favour maintaining immunosuppressive therapies during surgery. Further studies are needed to determine the optimal perioperative treatments required to limit post-operative inflammatory relapses.

External Evaluation of Population Pharmacokinetic Models and Bayes-Based Dosing of Infliximab

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from −7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of −0.74 to −0.29 mg/L and mean percent error of −16.6 to −0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.

Juvenile Idiopathic Arthritis-Associated Chronic Uveitis: Recent Therapeutic Approaches

Pediatric patients with early onset (before the age of 6 years), antinuclear antibody positive, oligoarticular or polyarticular juvenile idiopathic arthritis (JIA), and some children with no arthritis may develop chronic, anterior uveitis. Recent recommendations insist on the need to perform slit lamp examination every 3 months for at least 5 years in early onset JIA patients in order to diagnose uveitis before complications develop. Local steroid therapy is usually the first-line treatment. However, in patients requiring steroid eye drops for several months, systemic immunomodulatory therapy is indicated. Methotrexate (MTX) is then prescribed in most cases; however, some patients also need anti-tumor necrosis factor alpha monoclonal antibody therapy and, in some cases, other biologics to control uveitis and avoid long-term ocular damage. Expert ophthalmologists and pediatricians must be involved in taking care of such patients. Immunomodulatory treatment must not be too easily interrupted and may even be intensified in some cases, particularly if there is a need for optimal disease control before ophthalmologic surgery. In good responders to MTX and/or biologics, treatment must be maintained at least 1 year, possibly even 2 years after achieving remission before tapering treatment intensity.