Center variability in the prognostic value of a cumulative acute cellular rejection "A-score" for long-term lung transplant outcomes.

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

Effect of obesity treatment interventions in preschool children aged 2-6 years: a systematic review and meta-analysis.

OBJECTIVES: (1) To summarise the literature on the impact of paediatric weight management interventions on health outcomes in preschool age children with overweight or obesity and (2) to evaluate the completeness of intervention description and real-world applicability using validated tools. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, CINAHL, Cochrane Library and PsychInfo were searched between 10 March 2015 and 21 November 2021. ELIGIBILITY CRITERIA: Randomised controlled trials addressing weight management in preschool children (2-6 years) with overweight or obesity. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted key information from each study and assessed risk of bias. Random-effects meta-analysis was performed where there was evidence for homogeneous effects. The certainty of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Of the 16 908 studies retrieved, 9 trials (1687 participants) met the inclusion criteria. These interventions used motivational interviewing (MI) or multicomponent educational interventions related to health behaviour approaches and were 6-12 months in duration. All studies contained some risk of bias. A difference was found in the intervention groups compared with controls for body mass index (BMI) z score (mean difference -0.10, 95% CI -0.12 to -0.09; eight trials, 1491 participants; p<0.001; I2 68%), though there was substantial heterogeneity. There were no subgroup effects between studies using MI compared with studies using multicomponent interventions. The certainty of the evidence was considered low. The trials were reported in sufficient detail and were considered pragmatic. CONCLUSIONS: Paediatric weight management interventions delivered to the parents of young children with obesity result in small declines in BMI z score. The results should be interpreted cautiously as they were inconsistent and the quality of the evidence was low. PROSPERO REGISTRATION NUMBER: CRD42020166843.

Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies.

Sepsis is defined as organ dysfunction due to a dysregulated systemic host response to infection. During gram-negative bacterial infection and other acute illness such as absorption from the gut infection, lipopolysaccharide (LPS) is a major mediator in sepsis. LPS is able to trigger inflammation through both intracellular and extracellular pathways. Classical interactions between LPS and host cells first involve LPS binding to LPS binding protein (LBP), a carrier. The LPS-LBP complex then binds to a receptor complex including the CD14, MD2, and toll-like receptor 4 (TLR4) proteins, initiating a signal cascade which triggers the secretion of pro-inflammatory cytokines. However, it has been established that LPS is also internalized by macrophages and endothelial cells through TLR4-independent pathways. Once internalized, LPS is able to bind to the cytosolic receptors caspases-4/5 in humans and the homologous caspase-11 in mice. Bound caspases-4/5 oligomerize and trigger the assembly of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome followed by the activation of inflammatory caspase-1 resulting in subsequent release of interleukin-1ß. Caspases-4/5 also activate the perforin gasdermin D and purinergic receptor P2X7, inducing cell lysis and pyroptosis. Pyroptosis is a notable source of inflammation and damage to the lung endothelial barrier during sepsis. Thus, inhibition of caspases-4/5/1 or downstream effectors to block intracellular LPS signaling may be a promising therapeutic approach in adjunction with neutralizing extracellular LPS for treatment of sepsis.