A multifaceted cellular damage repair and prevention pathway promotes high-level tolerance to ß-lactam antibiotics.

Bactericidal antibiotics are powerful agents due to their ability to convert essential bacterial functions into lethal processes. However, many important bacterial pathogens are remarkably tolerant against bactericidal antibiotics due to inducible damage repair responses. The cell wall damage response two-component system VxrAB of the gastrointestinal pathogen Vibrio cholerae promotes high-level ß-lactam tolerance and controls a gene network encoding highly diverse functions, including negative control over multiple iron uptake systems. How this system contributes to tolerance is poorly understood. Here, we show that ß-lactam antibiotics cause an increase in intracellular free iron levels and collateral oxidative damage, which is exacerbated in the ∆vxrAB mutant. Mutating major iron uptake systems dramatically increases ∆vxrAB tolerance to ß-lactams. We propose that VxrAB reduces antibiotic-induced toxic iron and concomitant metabolic perturbations by downregulating iron uptake transporters and show that iron sequestration enhances tolerance against ß-lactam therapy in a mouse model of cholera infection. Our results suggest that a microorganism's ability to counteract diverse antibiotic-induced stresses promotes high-level antibiotic tolerance and highlights the complex secondary responses elicited by antibiotics.

Genetic Determinants of Penicillin Tolerance in Vibrio cholerae.

Many bacteria are resistant to killing (tolerant) by typically bactericidal antibiotics due to their ability to counteract drug-induced cell damage. Vibrio cholerae, the cholera agent, displays an unusually high tolerance to diverse inhibitors of cell wall synthesis. Exposure to these agents, which in other bacteria leads to lysis and death, results in a breakdown of the cell wall and subsequent sphere formation in V. cholerae Spheres readily recover to rod-shaped cells upon antibiotic removal, but the mechanisms mediating the recovery process are not well characterized. Here, we found that the mechanisms of recovery are dependent on environmental conditions. Interestingly, on agarose pads, spheres undergo characteristic stages during the restoration of rod shape. Drug inhibition and microscopy experiments suggest that class A penicillin binding proteins (aPBPs) play a more active role than the Rod system, especially early in sphere recovery. Transposon insertion sequencing (TnSeq) analyses revealed that lipopolysaccharide (LPS) and cell wall biogenesis genes, as well as the sigma E cell envelope stress response, were particularly critical for recovery. LPS core and O-antigen appear to be more critical for sphere formation/integrity and viability than lipid A modifications. Overall, our findings demonstrate that the outer membrane is a key contributor to beta lactam tolerance and suggest a role for aPBPs in cell wall biogenesis in the absence of rod-shape cues. Factors required for postantibiotic recovery could serve as targets for antibiotic adjuvants that enhance the efficacy of antibiotics that inhibit cell wall biogenesis.

Surgical Decision Making for Mild-to-Moderate Cubital Tunnel Syndrome.

Purpose: The management of ulnar neuropathy remains unclear as there are neither consensus guidelines nor compelling data available to inform optimal treatment. Identifying patients in the mild-to-moderate group that would benefit most from surgery is challenging as their symptoms can be subtle and less debilitating. This study investigated predictors of surgical intervention among patients presenting with McGowan mild or moderate cubital tunnel syndrome (CuTS). Methods: This is an institutional review board-approved study. Patients evaluated from March 2016 to July 2022 were included if they were diagnosed with McGowan mild or moderate CuTS and underwent concurrent electrodiagnostic and ultrasound evaluations. Patient demographics, symptom presentation, and clinical and diagnostic test findings were analyzed. Variables were analyzed using Student t test, Mann-Whitney U test, or Pearson's chi-square test. Multivariable logistic regression was used to assess the association of covariates and surgery. Results: Seventy-three patients and 103 elbows were identified. The mean age and body mass index were 51 years and 26.9, respectively. Most patients were men, right-handed, and unilaterally symptomatic in the dominant hand. Twenty-six elbows were surgically treated. Bivariable analyses by surgical treatment showed that patients who underwent surgery more often had positive electrodiagnostic findings including motor nerve conduction velocity <50 m/s and a >10 m/s conduction velocity difference across the forearm compared with elbow. Fifty-nine cases were categorized as electrodiagnostically normal. Of the electrodiagnostically normal cases, 29 had positive findings of CuTS on ultrasound. Logistic regression model showed that electrodiagnostically severe cases had 3.7 times higher odds of being surgically treated than normal counterparts (adjusted odds ratio, 3.7; 95% CI, 1.11-12.6; P = .03). Conclusions: Not many differences in objective findings identify patients who should receive operative treatment. In addition to test results, more subjective findings from patients such as patient-reported level of impairment may be able to bridge this gap in surgical decision making. Clinical relevance: This study contributes to treatment decision making for mild and moderate CuTS.

Procedure-Specific Complications Associated with Ultrasound-Guided Erector Spinae Plane Block for Lumbar Spine Surgery: A Retrospective Analysis of 342 Consecutive Cases.

Purpose: Presumed benefits of erector spinae plane blocks (ESPB) include an enhanced safety profile and few complications. There are few large series, which report the incidence of complications associated with ESPB on a procedure-specific basis. The objective of this retrospective cohort study was to estimate the incidence of complications of ESPB in a large series of patients undergoing lumbar spine surgery. Patients and Methods: We included 342 consecutive patients who underwent any primary lumbar spine surgery via posterior approach (November 2018-July 2020). All patients received bilateral ultrasound-guided ESPB. The primary study outcome was the incidence of any perioperative complication, defined a priori as sensory, motor, hematologic, hemodynamic or respiratory complication consistent with plausible contribution from the ESPB. Secondary outcomes included the incidence of numeric rating scale (NRS) pain scores ≥7 in the post anesthesia care unit (PACU) and risk factors associated with NRS ≥7 (age, sex, ASA class, BMI, opioid tolerance, surgical type, and duration). Results: We did not identify any pre-specified complications associated with ESPB. There was one unilateral pneumothorax, in one patient, deemed unlikely to have been related to ESPB. NRS ≥7 was found in 17/342 patients (5%) and was independent of any background differences or risk factors assessed. Conclusion: Ultrasound guided ESPB for lumbar spine surgery was associated with zero complications, no interference with intraoperative neuromonitoring or the early postoperative neurological examination, and low incidence of poorly controlled pain in the PACU. These results help to establish procedure-specific risks and benefits of ESPB for spine surgery.

Preoperative MRI-based vertebral bone quality (VBQ) score assessment in patients undergoing lumbar spinal fusion.

BACKGROUND CONTEXT: The importance of bone status assessment in spine surgery is well recognized. The current gold standard for assessing bone mineral density is dual-energy X-ray absorptiometry (DEXA). However, DEXA has been shown to overestimate BMD in patients with spinal degenerative disease and obesity. Consequently, alternative radiographic measurements using data routinely gathered during preoperative evaluation have been explored for the evaluation of bone quality and fracture risk. Opportunistic quantitative computed tomography (QCT) and more recently, the MRI-based vertebral bone quality (VBQ) score, have both been shown to correlate with DEXA T-scores and predict osteoporotic fractures. However, to date the direct association between VBQ and QCT has not been studied. PURPOSE: The objective of this study was to evaluate the correlation between VBQ and spine QCT BMD measurements and assess whether the recently described novel VBQ score can predict the presence of osteopenia/osteoporosis diagnosed with QCT. STUDY DESIGN/SETTING: Cross-sectional study using retrospectively collected data. PATIENT SAMPLE: Patients undergoing lumbar fusion from 2014-2019 at a single, academic institution with available preoperative lumbar CT and T1-weighted MRIs were included. OUTCOME MEASURES: Correlation of the VBQ score with BMD measured by QCT, and association between VBQ score and presence of osteopenia/osteoporosis. METHODS: Asynchronous QCT measurements were performed. The average L1-L2 BMD was calculated and patients were categorized as either normal BMD (>120 mg/cm3) or osteopenic/osteoporotic (≤120 mg/cm3). The VBQ score was calculated by dividing the median signal intensity of the L1-L4 vertebral bodies by the signal intensity of the cerebrospinal fluid on midsagittal T1-weighted MRI images. Inter-observer reliability testing of the VBQ measurements was performed. Demographic data and the VBQ score were compared between the normal and osteopenic/osteoporotic group. To determine the area-under-curve (AUC) of the VBQ score as a predictor of osteopenia/osteoporosis receiver operating characteristic (ROC) analysis was performed. VBQ scores were compared with QCT BMD using the Pearson's correlation. RESULTS: A total of 198 patients (53% female) were included. The mean age was 62 years and the mean BMI was 28.2 kg/m2. The inter-observer reliability of the VBQ measurements was excellent (ICC of 0.90). When comparing the patients with normal QCT BMD to those with osteopenia/osteoporosis, the patients with osteopenia/osteoporosis were significantly older (64.9 vs. 56.7 years, p<.0001). The osteopenic/osteoporotic group had significantly higher VBQ scores (2.6 vs. 2.2, p<.0001). The VBQ score showed a statistically significant negative correlation with QCT BMD (correlation coefficient = -0.358, 95% CI -0.473 - -0.23, p<.001). Using a VBQ score cutoff value of 2.388, the categorical VBQ score yielded a sensitivity of 74.3% and a specificity of 57.0% with an AUC of 0.7079 to differentiate patients with osteopenia/osteoporosis and with normal BMD. CONCLUSIONS: We found that the VBQ score showed moderate diagnostic ability to differentiate patients with normal BMD versus osteopenic/osteoporotic BMD based on QCT. VBQ may be an interesting adjunct to clinically performed bone density measurements in the future.