Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds.

Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum-sensing transcription factor MvfR (multiple virulence factor regulator) by interrogating, 5 days post-infection, its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs adenosine triphosphate generation, oxidative phosphorylation, and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR-mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients. IMPORTANCE: Skeletal muscle, pivotal for many functions in the human body, including breathing and protecting internal organs, contains abundant mitochondria essential for maintaining cellular homeostasis during infection. The effect of Pseudomonas aeruginosa (PA) infections on skeletal muscle remains poorly understood. Our study delves into the role of a central quorum-sensing transcription factor, multiple virulence factor regulator (MvfR), that controls the expression of multiple acute and chronic virulence functions that contribute to the pathogenicity of PA. The significance of our study lies in the role of MvfR in the metabolic perturbances linked to mitochondrial functions in skeletal muscle and the effectiveness of the novel MvfR inhibitor and the mitochondrial-targeted peptide SS-31 in alleviating the mitochondrial disturbances caused by PA in skeletal muscle. Inhibiting MvfR or interfering with its effects can be a potential therapeutic strategy to curb PA virulence.

Skeletal Muscle Mitochondrial Dysfunction Mediated by Pseudomonas aeruginosa Quorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds.

Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum sensing (QS) transcription factor MvfR by interrogating five days post-infection its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs ATP generation, oxidative phosphorylation (OXPHOS), and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR- mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.

The Effect of Language on Access to Timely COVID-19 Vaccination of Solid Abdominal Organ Transplant Recipients.

In dynamic healthcare environments including the COVID-19 pandemic, it is paramount to communicate health recommendations expediently and clearly. Research has shown social determinants of health affect the impact of COVID-19 on abdominal transplant recipients, but there has been less research on the effect of language proficiency. This is a cohort study of time to first COVID-19 vaccination among abdominal organ transplant recipients in an academic medical center in Boston, MA between 18 December 2020, and 15 February 2021. Cox proportional hazards analysis of time to vaccination by preferred language were adjusted for race, age group, insurance, and transplanted organ. Among 3001 patients, 53% were vaccinated during the study period. Language preference other than English was independently associated with delay to vaccination (0.64, p = 0.001), on adjusted analysis. In addition, Black, Hispanic and other race patients were less likely to be vaccinated than white patients (0.58, 0.67, 0.68 vs. reference, all p < 0.03). Language preference other than English is an independent barrier to solid abdominal organ transplant recipients' access to timely COVID-19 vaccination. Equity in care should be improved by providing targeted services to minority language speakers.

Trauma patients with limited English proficiency: Outcomes from two level one trauma centers.

BACKGROUND: Outcomes for surgical patients with limited English proficiency (LEP) may be worse compared to patients with English proficiency. We sought to evaluate the association of LEP with outcomes for trauma patients. METHODS: Admitted adult patients on trauma service at two Level One trauma centers from 2015 to 2019 were identified. RESULTS: 12,562 patients were included in total; 7.3% had LEP. On multivariable analyses, patients with LEP had lower odds of discharge to post-acute care versus home compared to patients with English proficiency (OR 0.69; 95% CI 0.58-0.83; p < 0.001) but had similar length of stay (Beta coefficient 1.16; 95% CI 0.00-2.32; p = 0.05), and 30-day readmission (OR 1.08; 95% CI 0.87-1.35; p = 0.46). CONCLUSIONS: Trauma patients with LEP had comparable short-term outcomes to English proficient patients but were less likely to be discharged to post-acute care facilities. The role of structural barriers, family preferences, and other factors merit future investigation.

Increasing Frequency of Interpreting Services is Associated With Shorter Peri-operative Length of Stay.

BACKGROUND: Patients with limited English proficiency have barriers to accessing care. Rather than a binary use or no use, this study uses granular data on frequency of interpreting services to determine if this frequency is associated with differences in peri-operative length of stay for patients with limited English proficiency. MATERIALS AND METHODS: This is a cross sectional study on length of stay for peri-operative admissions of at least one night during 2018, for patients who used medical interpreting services in an academic medical center in Boston, Massachusetts. The participants are split into quartiles of ascending number of interpreting events per day. The exposure for the primary outcome is the frequency of interpreting events per day during peri-operative admission. The primary study outcome measurement is peri-operative length of stay in days. RESULTS: There was a statistically significant decrease in length of stay for patients in the highest two quartiles of interpreting service frequency, compared to the lowest quartile: quartile 2 trended shorter by 1.4 d (95% CI -4.5 to 1.7, P = 0.37), quartile 3 was 4.2 d shorter (95% CI -7.6 to -0.7, P = 0.02), and quartile 4 was 4.6 d shorter (95% CI -8.1 to -1.1, P = 0.01). CONCLUSIONS: More frequent interpreting services per day during peri-operative admission are associated with shorter length of stay in adjusted analysis. The findings merit further study in an intervention to increase use of interpreting services for surgical patients with limited English proficiency to study the impact of increased frequency of culturally competent care.

Prehospital hypertonic fluid resuscitation for trauma patients: A systematic review and meta-analysis.

BACKGROUND: Prehospital assessment of a patient's circulation status and appropriate resuscitation with intravenous fluids plays a critical role in patients with obvious hemorrhage or systolic blood pressure below 90 mm Hg. OBJECTIVES: We assessed the efficacy and safety of prehospital administration of crystalloids or colloids to improve the survival rate of trauma patients with acceptable safety profile. DATA SOURCES: We searched SCOPUS, Embase, TRIP database, Cochrane Central Register of Controlled Trials, Ovid MEDLINE, and PubMed as per search protocol from January 1, 1900 to February 12, 2015. STUDY ELIGIBILITY CRITERIA: All randomized controlled trials were considered. PARTICIPANTS AND INTERVENTIONS: All patients had penetrating or blunt trauma, excluding traumatic brain or thermal injuries. At least one of the comparators should be a crystalloid or colloid. STUDY APPRAISAL AND SYNTHESIS METHODS: Detailed search strategy was developed and utilized. Duplicates were removed from the search results. We, the co-first authors (C.d.C. and F.G.), independently reviewed the article titles and abstracts to assess eligibility. Eligible articles were downloaded for full text review to determine inclusion in the review and analysis. We (C.d.C. and F.G.) performed a methodological quality assessment of each included article. The primary outcome was mortality. The secondary outcomes included adverse events, infections, multiple organ dysfunction score, and length of stay at the hospital. Heterogeneity was measured by I value. An I value greater than 50% was considered to be substantial heterogeneity. Fixed effect analysis and random effect analysis were performed when needed. RESULTS: A total of nine trials (3,490 patients) were included in the systematic review, and six trials were included in meta-analyses. There were no significant differences between hypertonic saline with dextran and lactated Ringer's solution in 1 day using two studies (2.91; 95% CI, 0.58-14.54; p = 0.19) and 28- to 30-day survival rates using another two studies (1.47; 95% CI, 0.30-7.18; p = 0.63). Adding dextran to hypertonic saline did not increase the survival rate (0.94; 95% CI, 0.65-1.34; p = 0.71). Overall, complications were comparable between all groups. LIMITATIONS: The quality of some of the included studies is not optimal. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: There is no beneficial effect of hypertonic saline with or without dextran in general traumatic patients. Further trials to evaluate its benefit in patients with penetrating trauma requiring surgery are warranted. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level I.