Citations

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient β-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for β-cell identity. Atf4-deficient β-cells down-regulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for β-cell identity and function under high glucose. But Atf4 activation paradoxically induces β-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect β-cells from metabolic stress-induced failure.

Background Bacteremia is sometimes observed in patients with prosthetic joint infection (PJI), and it is associated with a lower likelihood of infection control. However, the prevalence and association of bacteremia in chronic PJI remain unknown. Questions/purposes (1) What percentage of patients are diagnosed with bacteremia at the time of hospital admission and before surgery for chronic PJI? (2) What clinical factors are associated with positive blood cultures? (3) To what degree are positive blood cultures associated with infection-free implant survival in patients with chronic PJI? Methods This prospective study was conducted at a single academic institution from June 2021 to August 2022. Within the study period, we treated 124 patients for chronic PJI, defined according to the modified Musculoskeletal Infection Society (MSIS) criteria. Of those, we considered patients who underwent revision surgery because of chronic PJI of the hip or knee as potentially eligible. All patients received two blood cultures within 48 hours after admission but before surgery. The second blood culture was performed on the contralateral arm 1 hour after the first was completed. Based on that, 87% (108 of 124) of patients were eligible; 13% (16 of 124) were excluded because of delayed blood sample transfers in 6% (7 of 124) of patients, contaminated samples in 2% (2 of 124), late hematogenous infection in 2% (3 of 124), and antibiotic use within 2 weeks before sampling in 3% (4 of 124). No patients were lost before the minimum study follow-up of 2 years without having reached a study endpoint (reinfection or persistent PJI) or had incomplete datasets, leaving 74% (92 of 124) for analysis here. The median (range) time from the index surgery (previous primary, debridement, or revision procedure) to the current revision for PJI in these patients was 16 months (2 to 180). Of the included patients, 40% (37 of 92) were men, 39% (36 of 92) had PJI of the hip, and 61% (56 of 92) had PJI of the knee. The mean age of patients was 65 ± 13 years, and the mean BMI was 28 ± 3 kg/m2. The interval between two cultures was at least 1 hour, and one culture was taken from each of the patient’s arms. Patients were divided into blood culture–positive and blood culture–negative groups based on preoperative blood culture results. The chi-square test and the independent t-test were used to compare demographic characteristics (gender, age, BMI, and affected joint) and clinical factors (American Society of Anesthesiologists [ASA] classification, hematological tests, comorbidities) between the two groups. Further multivariable logistic regression analysis was performed to assess the factors associated with positive blood cultures, which controlled for potential confounders including age, gender, BMI, and affected joint. The Firth penalized likelihood was employed when there was monotone likelihood in logistic regression analysis to reduce small-sample bias. A Kaplan-Meier curve tracked infection-free implant survival over 30 months, with differences evaluated using the log-rank test. Results Overall, 15% (14 of 92) of patients had positive blood cultures. After adjusting for age, gender, infection site, BMI, and intraoperative isolation of gram-positive cocci, we found that patients classified as ASA III (OR 4 [95% confidence interval (CI) 1 to 21]; p = 0.04) and those who had diabetes (OR 14 [95% CI 3 to 100]; p < 0.001) had a higher odds of positive blood cultures. We found no difference in the Kaplan-Meier estimate for infection-free implant survival at 30 months between those with positive blood cultures (86% [95% CI 76% to 95%]) and those with negative blood cultures (91% [95% CI 88% to 94%]; p = 0.51). Conclusion In this prospective, observational study, we found that chronic PJI can potentially lead to hematogenous dissemination of pathogens, particularly in patients with poor overall health (such as those classified as ASA III and patients diagnosed with diabetes). Therefore, selective preoperative blood cultures may be crucial in helping clinicians implement early intervention measures to prevent the serious consequences of bacteremia in patients with poor baseline health and those with other implanted devices. Larger studies with longer follow-up are needed to further validate these findings, ensure more robust estimates, and conduct comprehensive evaluations of the risk factors associated with positive blood cultures in chronic PJI. Level of Evidence Level II, therapeutic study.

R47H- TREM2 mutation enhances AKT signaling in human AD microglia and mediates proinflammatory and synaptic toxicity in a tauopathy mouse model.

Abstract Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut. Conclusions: This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.