BACKGROUND:Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS:We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS:Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197-331), and remnant cholesterol was 53 mg/dL (interquartile range, 38-76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2-213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, -3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS:Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05610280.
Background:Critically ill patients are at risk of nosocomial infections, acquisition of multidrug-resistant pathogens, and substantial antimicrobial consumption. We assessed whether bathing with chlorhexidine reduces these outcomes compared to standard practices. Methods:We conducted an open-label, cluster-randomised crossover trial in 22 Brazilian intensive care units comparing daily chlorhexidine bathing versus soap and water bathing (control). Centres were randomised to 3- or 6-months chlorhexidine or control periods, separated by a 1-month washout. Primary outcome was nosocomial infection rate (central line-associated bloodstream infections, catheter-associated urinary tract infections, and ventilator-associated pneumonia) during ICU stay. Secondary outcomes included specific nosocomial infections incidence, multi-drug resistant cultures, antibiotic use, length of stay, and mortality. This completed trial is registered at ClinicalTrials.gov, NCT05485051. Findings:From August 1st, 2022 to December 31, 2023, we included 15,935 patients (8247 chlorhexidine and 7688 control group). Mean age was 64·4 years (SD 17·3) in the chlorhexidine group [4315 (52·3%) male] and 64·2 years (SD 17·4) in the control group [4035 (52·5%) male]. A total of 201 nosocomial infections occurred in the chlorhexidine group, compared to 165 in the control group. There was no statistically significant difference in the overall nosocomial infections rate between groups [3·99 per 1000 patient-days in the chlorhexidine group and 3·45 per 1000 patient-days in the control group (rate-ratio, 1·09; 95% CI 0·95-1·25; p = 0·22)]. Patients in the chlorhexidine group had lower rates of multi-drug resistant cultures compared to the control group (14·42 vs. 20·13 per 1000 patient-days, rate-ratio, 0·73; 95% CI 0·59-0·91; p = 0·0092). Although overall antimicrobial consumption defined by WHO's DDD did not differ between groups (rate-ratio, 0·91; 95% CI 0·80-1·03; p = 0·14), there was a statistically significant difference in the consumption of antimicrobials in the Reserve group of WHO's AWaRe classification (rate-ratio, 0·73; 95% CI 0·59-0·90; p = 0·0071) in the chlorhexidine group. This reduction was not associated with higher mortality. Interpretation:Chlorhexidine bathing did not reduce the incidence of nosocomial infections in a general ICU population, but contributed to lower rates of multi-drug resistant pathogen isolation, and lower use of Reserve antimicrobials, potentially leading to a qualitative modification of antimicrobial use. Funding:This study was funded by the Brazilian Health Ministry through the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde (PROADI-SUS).
In a recent study, Adler and colleagues demonstrated that microglia regulate blood glucose delivery to fuel the astrocyte-neuron lactate shuttle. As neuronal protein translation supported by this mechanism is essential for motor learning, these findings reveal how coordinated interactions among microglia, astrocytes, and neurons orchestrate neuroenergetics to support cognition.
