Structural Patching Fosters Divergence of Mitochondrial Ribosomes.

Mitochondrial ribosomes (mitoribosomes) are essential components of all mitochondria that synthesize proteins encoded by the mitochondrial genome. Unlike other ribosomes, mitoribosomes are highly variable across species. The basis for this diversity is not known. Here, we examine the composition and evolutionary history of mitoribosomes across the phylogenetic tree by combining three-dimensional structural information with a comparative analysis of the secondary structures of mitochondrial rRNAs (mt-rRNAs) and available proteomic data. We generate a map of the acquisition of structural variation and reconstruct the fundamental stages that shaped the evolution of the mitoribosomal large subunit and led to this diversity. Our analysis suggests a critical role for ablation and expansion of rapidly evolving mt-rRNA. These changes cause structural instabilities that are "patched" by the acquisition of pre-existing compensatory elements, thus providing opportunities for rapid evolution. This mechanism underlies the incorporation of mt-tRNA into the central protuberance of the mammalian mitoribosome, and the altered path of the polypeptide exit tunnel of the yeast mitoribosome. We propose that since the toolkits of elements utilized for structural patching differ between mitochondria of different species, it fosters the growing divergence of mitoribosomes.

MAN VERSUS MACHINE: PROVIDER DIRECTED VERSUS PRECISION AUTOMATED CRITICAL CARE MANAGEMENT IN A PORCINE MODEL OF DISTRIBUTIVE SHOCK.

ABSTRACT: Background: Critical care management of shock is a labor-intensive process. Precision Automated Critical Care Management (PACC-MAN) is an automated closed-loop system incorporating physiologic and hemodynamic inputs to deliver interventions while avoiding excessive fluid or vasopressor administration. To understand PACC-MAN efficacy, we compared PACC-MAN to provider-directed management (PDM). We hypothesized that PACC-MAN would achieve equivalent resuscitation outcomes to PDM while maintaining normotension with lower fluid and vasopressor requirements. Methods : Twelve swine underwent 30% controlled hemorrhage over 30 min, followed by 45 min of aortic occlusion to generate a vasoplegic shock state, transfusion to euvolemia, and randomization to PACC-MAN or PDM for 4.25 h. Primary outcomes were total crystalloid volume, vasopressor administration, total time spent at hypotension (mean arterial blood pressure <60 mm Hg), and total number of interventions. Results : Weight-based fluid volumes were similar between PACC-MAN and PDM; median and IQR are reported (73.1 mL/kg [59.0-78.7] vs. 87.1 mL/kg [79.4-91.8], P = 0.07). There was no statistical difference in cumulative norepinephrine (PACC-MAN: 33.4 µg/kg [27.1-44.6] vs. PDM: 7.5 [3.3-24.2] µg/kg, P = 0.09). The median percentage of time spent at hypotension was equivalent (PACC-MAN: 6.2% [3.6-7.4] and PDM: 3.1% [1.3-6.6], P = 0.23). Urine outputs were similar between PACC-MAN and PDM (14.0 mL/kg vs. 21.5 mL/kg, P = 0.13). Conclusion : Automated resuscitation achieves equivalent resuscitation outcomes to direct human intervention in this shock model. This study provides the first translational experience with the PACC-MAN system versus PDM.

A Comparative Analysis of "Surgery First" vs. "Endoscopy First" for Pediatric Choledocholithiasis Presenting at the End of the Week.

BACKGROUND: Choledocholithiasis in children is commonly managed with an "endoscopy first" (EF) strategy (endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy (LC) under a separate anesthetic). Endoscopic Retrograde Cholangiopancreatography is limited at the end of the week (EoW). We hypothesize that a "surgery first" (SF) approach with LC, intraoperative cholangiogram (IOC), and possible laparoscopic common bile duct exploration (LCBDE) can decrease length of stay (LOS) and time to definitive intervention (TTDI). METHODS: This is a retrospective single-center cohort study conducted between 2018 and 2023 in pediatric patients with suspected choledocholithiasis. Work week (WW) presentation included admission between Monday and Thursday. Time to definitive intervention was defined as time to LC. RESULTS: 88 pediatric patients were identified, 61 managed with SF (33 WW and 28 EoW) and 27 managed with EF (18 WW and 9 EoW). Both SF groups had shorter mean LOS for WW and EoW presentation (64.5 h, 92.4 h, 112.9 h, and 113.0 h; P < .05). There was a downtreading TTDI in the SF groups (SF: WW 24.7 h and EoW 21.7 h; EF: WW 31.7 h and EoW 35.9 h; P = .11). 44 patients underwent LCBDE with similar success rates (91.6% WW and 85% EoW; P = 1.0). All EF patients received 2 procedures; 69% of SF patients were definitively managed with one. CONCLUSION: Children with choledocholithiasis at the EoW have a longer LOS and TTDI. These findings are amplified when children enter an EF treatment pathway. An SF approach results in shorter LOS with fewer procedures, regardless of the time of presentation.