Search

Background: The incidence of severe injury in the geriatric population is increasing. However, the impact of frailty on long-term outcomes after injury in this population remains understudied. Therefore, we aimed to understand the impact of frailty on long-term functional outcomes of severely injured geriatric patients., Methods: We conducted a retrospective cohort study, including patients ≥65 years old with an Injury Severity Score ≥15, who were admitted between December 2015 and April 2022 at one of 3 level 1 trauma centers in our region. Patients were contacted between 6 and 12 months postinjury and administered a trauma quality of life survey, which assessed for the presence of new functional limitations in their activities of daily living. We defined frailty using the mFI-5 validated frailty tool: patients with a score ≥2 out of 5 were considered frail. The impact of frailty on long-term functional outcomes was assessed using 1:1 propensity matching adjusting for patient characteristics, injury characteristics, and hospital site., Results: We included 580 patients, of whom 146 (25.2%) were frail. In a propensity-matched sample of 125 pairs, frail patients reported significantly higher functional limitations than nonfrail patients (69.6% vs 47.2%; P < .001). This difference was most prominent in the following activities: climbing stairs, walking on flat surfaces, going to the bathroom, bathing, and cooking meals. In a subgroup analysis, frail patients with traumatic brain injuries experienced significantly higher long-term functional limitations., Conclusion: Frail geriatric patients with severe injury are more likely to have new long-term functional outcomes and may benefit from screening and postdischarge monitoring and rehabilitation services., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: General surgery procedures place stress on geriatric patients, and postdischarge care options should be evaluated. We compared the association of discharge to a skilled nursing facility (SNF) versus home on patient readmission., Methods: We retrospectively reviewed the Nationwide Readmission Database (2016-2019) and included patients ≥65 y who underwent a general surgery procedure between January and September. Our primary outcome was 30-d readmissions. Our secondary outcome was predictors of readmission after discharge to an SNF. We performed a 1:1 propensity-matched analysis adjusting for patient demographics and hospital course to compare patients discharged to an SNF with patients discharged home. We performed a sensitivity analysis on patients undergoing emergency procedures and a stepwise regression to identify predictors of readmission., Results: Among 140,056 included patients, 33,916 (24.2%) were discharged to an SNF. In the matched population of 19,763 pairs, 30-d readmission was higher in patients discharged to an SNF. The most common diagnosis at readmission was sepsis, and a greater proportion of patients discharged to an SNF were readmitted for sepsis. In the sensitivity analysis, emergency surgery patients discharged to an SNF had higher 30-d readmission. Higher illness severity during the index admission and living in a small or fringe county of a large metropolitan area were among the predictors of readmission in patients discharged to an SNF, while high household income was protective., Conclusions: Discharge to an SNF compared to patients discharged home was associated with a higher readmission. Future studies need to identify the patient and facility factors responsible for this disparity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Prolonged exposure to elevated free fatty acids induces β-cell failure (lipotoxicity) and contributes to the pathogenesis of type 2 diabetes. In vitro exposure of β-cells to the saturated free fatty acid palmitate is a valuable model of lipotoxicity, reproducing features of β-cell failure observed in type 2 diabetes. In order to map the β-cell response to lipotoxicity, we combined RNA-sequencing of palmitate-treated human islets with iTRAQ proteomics of insulin-secreting INS-1E cells following a time course exposure to palmitate., Results: Crossing transcriptome and proteome of palmitate-treated β-cells revealed 85 upregulated and 122 downregulated genes at both transcript and protein level. Pathway analysis identified lipid metabolism, oxidative stress, amino-acid metabolism and cell cycle pathways among the most enriched palmitate-modified pathways. Palmitate induced gene expression changes compatible with increased free fatty acid mitochondrial import and β-oxidation, decreased lipogenesis and modified cholesterol transport. Palmitate modified genes regulating endoplasmic reticulum (ER) function, ER-to-Golgi transport and ER stress pathways. Furthermore, palmitate modulated cAMP/protein kinase A (PKA) signaling, inhibiting expression of PKA anchoring proteins and downregulating the GLP-1 receptor. SLC7 family amino-acid transporters were upregulated in response to palmitate but this induction did not contribute to β-cell demise. To unravel critical mediators of lipotoxicity upstream of the palmitate-modified genes, we identified overrepresented transcription factor binding sites and performed network inference analysis. These identified LXR, PPARα, FOXO1 and BACH1 as key transcription factors orchestrating the metabolic and oxidative stress responses to palmitate., Conclusions: This is the first study to combine transcriptomic and sensitive time course proteomic profiling of palmitate-exposed β-cells. Our results provide comprehensive insight into gene and protein expression changes, corroborating and expanding beyond previous findings. The identification of critical drivers and pathways of the β-cell lipotoxic response points to novel therapeutic targets for type 2 diabetes.

Commensal and pathogenic enteric bacteria have developed several systems to adapt to proton leakage into the cytoplasm resulting from extreme acidic conditions. One such system involves arginine uptake followed by export of the decarboxylated product agmatine, carried out by the arginine/agmatine antiporter (AdiC), which thus works as a virtual proton pump. Here, using classical and targeted molecular dynamics, we investigated at the atomic level the mechanism of arginine transport through AdiC of E. coli. Overall, our MD simulation data clearly demonstrate that global rearrangements of several transmembrane segments are necessary but not sufficient for achieving transitions between structural states along the arginine translocation pathway. In particular, local structural changes, namely rotameric conversions of two aromatic residues, are needed to regulate access to both the outward- and inward-facing states. Our simulations have also enabled identification of a few residues, overwhelmingly aromatic, which are essential to guiding arginine in the course of its translocation. Most of them belong to gating elements whose coordinated motions contribute to the alternating access mechanism. Their conservation in all known E. coli acid resistance antiporters suggests that the transport mechanisms of these systems share common features. Last but not least, knowledge of the functional properties of AdiC can advance our understanding of the members of the amino acid-carbocation-polyamine superfamily, notably in eukaryotic cells.

Many plasma membrane transporters are downregulated by ubiquitylation, endocytosis, and delivery to the lysosome in response to various stimuli. We report here that two amino acid transporters of Saccharomyces cerevisiae, the general amino acid permease (Gap1) and the arginine-specific permease (Can1), undergo ubiquitin-dependent downregulation in response to their substrates and that this downregulation is not due to intracellular accumulation of the transported amino acids but to transport catalysis itself. Following an approach based on permease structural modeling, mutagenesis, and kinetic parameter analysis, we obtained evidence that substrate-induced endocytosis requires transition of the permease to a conformational state preceding substrate release into the cell. Furthermore, this transient conformation must be stable enough, and thus sufficiently populated, for the permease to undergo efficient downregulation. Additional observations, including the constitutive downregulation of two active Gap1 mutants altered in cytosolic regions, support the model that the substrate-induced conformational transition inducing endocytosis involves remodeling of cytosolic regions of the permeases, thereby promoting their recognition by arrestin-like adaptors of the Rsp5 ubiquitin ligase. Similar mechanisms might control many other plasma membrane transporters according to the external concentrations of their substrates., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Amino acid uptake in yeast cells is mediated by about 16 plasma membrane permeases, most of which belong to the amino acid-polyamine-organocation (APC) transporter family. These proteins display various substrate specificity ranges. For instance, the general amino acid permease Gap1 transports all amino acids, whereas Can1 and Lyp1 catalyze specific uptake of arginine and lysine, respectively. Although Can1 and Lyp1 have different narrow substrate specificities, they are close homologs. Here we investigated the molecular rules determining the substrate specificity of the H(+)-driven arginine-specific permease Can1. Using a Can1-Lyp1 sequence alignment as a guideline and a three-dimensional Can1 structural model based on the crystal structure of the bacterial APC family arginine/agmatine antiporter, we introduced amino acid substitutions liable to alter Can1 substrate specificity. We show that the single substitution T456S results in a Can1 variant transporting lysine in addition to arginine and that the combined substitutions T456S and S176N convert Can1 to a Lyp1-like permease. Replacement of a highly conserved glutamate in the Can1 binding site leads to variants (E184Q and E184A) incapable of any amino acid transport, pointing to a potential role for this glutamate in H(+) coupling. Measurements of the kinetic parameters of arginine and lysine uptake by the wild-type and mutant Can1 permeases, together with docking calculations for each amino acid in their binding site, suggest a model in which residues at positions 176 and 456 confer substrate selectivity at the ligand-binding stage and/or in the course of conformational changes required for transport.