Galacto-Oligosaccharide Supplementation Modulates Pathogen-Commensal Competition between Streptococcus agalactiae and Streptococcus salivarius.

The members of the infant microbiome are governed by feeding method (breastmilk vs. formula). Regardless of the source of nutrition, a competitive growth advantage can be provided to commensals through prebiotics - either human milk oligosaccharides (HMOs) or plant oligosaccharides that are supplemented into formula. To characterize how prebiotics modulate commensal - pathogen interactions, we have designed and studied a minimal microbiome where a pathogen, Streptococcus agalactiae engages with a commensal, Streptococcus salivarius. We discovered that while S. agalactiae suppresses the growth of S. salivarius via increased lactic acid production, galacto-oligosaccharides (GOS) supplementation reverses the effect. This result has major implications in characterizing how single species survive in the gut, what niche they occupy, and how they engage with other community members.

Sialylated variants of lacto-N-tetraose exhibit antimicrobial activity against Group B Streptococcus.

Human milk oligosaccharides (HMOs) possess antimicrobial activity against a number of bacterial pathogens. HMOs prevent infection by serving as decoy receptors that competitively bind pathogens thus preventing pathogen attachment to host epithelial cell receptors. In a second mechanistic pathway, we recently demonstrated that heterogenous HMO extracts exert antimicrobial action against Group B Streptococcus by increasing cellular permeability. As human milk contains ca. 200 unique glycans however, our understanding of which pharmacophores are most important to HMO antimicrobial activity remains immature. In the present study, we describe the first evaluation of the antimicrobial and antibiofilm activities of five structurally defined, ubiquitous sialylated HMOs against Group B Streptococcus.

The Utility of the Plastic Surgery Standardized Letter of Recommendation Form in Predicting Residency Match Outcomes.

BACKGROUND: Letters of recommendation play an important role in resident selection. While plastic surgery's Standardized Letter of Recommendation (SLOR) form most commonly serves as an adjunct to narrative letters, the SLOR provides objective data in the review process and could eventually replace narrative letters. The utility of the SLOR in predicting Match outcomes has not been studied. METHODS: Applicant data from 225 first-time residency applicants in 2020-21 were collected. Logistic regression modeling was used to predict Match outcomes. This model was validated using 100 randomly selected applicants from 2019-20. RESULTS: Rank placement (SLOR Question 6) was the most important factor when predicting Match outcomes (p<0.0001). All other SLOR questions were not predictive and subject to notable score inflation. No SLOR score differences were noted based on race; female applicants were rated higher in two of ten domains (p<0.05). CONCLUSIONS: One question on the plastic surgery SLOR was highly predictive of an applicant matching. However, the remaining SLOR questions had little utility and were subject to gross score inflation. Further work should be done to optimize the utility of the SLOR in differentiating applicants. This has important implications in ensuring the selection of professional, competent residents according to the aims of the Accreditation Council of Graduate Medical Education.

The role of traditional social determinants of health in referral patterns, timing of surgery, and Chiari Health Index for Pediatrics-determined quality of life in children with symptomatic Chiari type I malformation.

OBJECTIVE: Understanding the impact of the social determinants of health on the utilization of healthcare resources is an important step in eliminating inequalities. The goal of this study was to determine the role of social determinants of health in referral patterns, timing of consultation/intervention, and quality of life in children with Chiari malformation type I (CM-I). METHODS: A retrospective study was conducted of children aged 0 to 18 years who underwent surgical treatment for CM-I at a single pediatric facility from 2015 to 2019. The variables included demographic and socioeconomic characteristics, referral patterns, timing, and quality of life data based on the Chiari Health Index for Pediatrics (CHIP). RESULTS: The cohort consisted of 103 surgically treated CM-I patients. No differences were seen in race, sex, insurance, or household income when evaluating referral source (community, specialist, or emergency department) or when comparing patients with incidental versus symptomatic findings. In the evaluation of timing from initial evaluation to surgery, no statistical differences were seen between racial, sex, insurance status, or income groups. Children from households of lower median family income were significantly more likely to report pain at the time of consultation (pain group median [interquartile range] $46,660 [$41,004-$50,367] vs nonpain group $53,604 [$41,427-$59,828], p = 0.004). Those in the lower-income group also reported lower CHIP scores corresponding to increased symptomatology in the nonpain physical symptoms (p = 0.004) and psychosocial domains (p = 0.018). CONCLUSIONS: There was no evidence of a difference in referral patterns or a delay in time from clinic presentation to surgery based on the traditional social determinants of health categories. Children from households in the lower-income group were associated with increased severity of pain and nonpain symptoms.

Impact of neurovascular comorbidities and complications on outcomes after procedural management of arteriovenous malformations.

OBJECTIVE: Cerebral arteriovenous malformations (AVMs) are complex vascular lesions at perpetual risk for rupture, which can lead to significant morbidity and mortality. This study sought to evaluate the dynamic relationship between comorbidities and post-procedure complications to quantify the risk of poor discharge outcomes to create a predictive outcomes model. METHODS: The National Inpatient Sample (NIS) data from 2012 to 2015 was queried for AVM treatment using International Classification of Diseases, Ninth Revision codes. The Neurovascular Comorbidities Index (NCI) quantified patient comorbidity burden. In-hospital complications included surgical and medical complications or seizures. The primary outcome was the NIS Subarachnoid Hemorrhage Outcome Measure (NIS-SOM). RESULTS: A total of 1363 patients were included. A total of 1330 patients (98%) underwent embolization, 28 (2%) underwent resection, and 9 (0.7%) underwent radiosurgery. A higher NCI was associated with the occurrence of any complication (odds ratio [OR], 1.30 if NCI = 2; P < 0.001). Higher NCI was also significantly associated with a poor NIS-SOM outcome (OR, 2.45 if NCI = 2 and no complications; P < 0.001). A ruptured AVM with intracranial hemorrhage (ICH) increased the risk of in-hospital complications (OR, 2.16; P = 0.007) and a poor NIS-SOM outcome (OR, 3.18; P < 0.001). Various hypothetical patient scenarios and the predicted outcomes are also presented. CONCLUSION: Neurovascular comorbidities have a significant impact on poor functional outcomes at discharge in patients with and without complications following procedural management of AVMs. At the time of initial patient assessment, risk stratification strategies should take into account neurovascular comorbidities and potential complications. Such an approach would ultimately optimize patient outcomes and increase the value of care provided.

Successful prevention of secondary burn progression using infliximab hydrogel: A murine model.

INTRODUCTION: Burn injury remains a serious cause of morbidity and mortality worldwide. Severity of burns is determined by the percentage of burned area compared to the body surface area, age of patient, and by the depth of skin and soft tissue involvement; these factors determine management as well as prospective outcomes. The pathophysiology of partial- to full-thickness burn conversion remains poorly understood and is associated with a worse overall prognosis. Recent studies have demonstrated that an altered inflammatory response may play a significant role in this conversion and therefore a reduction in early inflammation is crucial to ultimately decreasing burn severity and morbidity. We hypothesize that the application of a microcapillary gelatin-alginate hydrogel loaded with anti-TNF-α (infliximab) monoclonal antibodies to a partial-thickness burn will reduce inflammation within partially burned skin and prevent further progression to a full-thickness burn. METHODS: Assembly of the microfluidic hydrogels is achieved by embedding microfibers within a hydrogel scaffold composed of a gelatin-alginate blend, which is then soaked in a solution containing anti-TNF-α antibodies for drug loading. 12 young (2-4 months) and 12 old (>16 months) mice were given partial thickness burns. The treatment cohort received the anti-TNF-α infused hydrogel with an occlusive dressing and the control cohort only received an occlusive dressing. Mice were euthanized at post-burn day 3 and skin samples were taken. Burn depth was evaluated using Vimentin immunostaining. RESULTS: All mice in the treatment cohort demonstrated decreased conversion of burn from partial to full thickness injury (old = p < 0.01, young = p < 0.001) as compared to the control group. Old mice had greater depth of burn than young mice (p < 0.001). There were greater eosinophils in the treatment cohort for both young and old mice, but it did not reach statistical significance. CONCLUSION: The application of a novel microcapillary gelatin-alginate hydrogel infused with anti-TNF-α antibody to partial thickness burns in mice showed reduction in partial to full thickness burn secondary progression as compared to controls using this murine model; this promising finding might help decrease the high morbidity and mortality associated with burn injuries.

Impact of Thrombocytopenia on Preoperative Hematoma Expansion for Acute Traumatic Subdural Hematoma.

BACKGROUND: Acute subdural hematoma is a neurosurgical emergency. Thrombocytopenia poses a management challenge for these patients. We aimed to determine the impact of thrombocytopenia on preoperative hemorrhage expansion and postoperative outcomes. METHODS: This retrospective study evaluated patients presenting at our institution with acute subdural hematoma between 2009 and 2019. Patients who underwent surgery, had thrombocytopenia (platelets <150,000/µL), and had multiple preoperative computed tomography scans were included. Case control 1:1 matching was performed to generate a matched cohort with no thrombocytopenia. Univariate analyses were conducted to determine changes in subdural thickness and midline shift, postoperative Glasgow Coma Scale score, mortality, length of stay, and readmission rates. RESULTS: We identified 19 patients with both thrombocytopenia and multiple preoperative computed tomography scans. Median platelet count was 112,000/µL (Q1 69,000, Q3 127,000). Comparing the thrombocytopenia cohort with the control group, there was a statistically significant difference in change in subdural thickness (median 5 mm [Q1 2, Q3 7.4] vs. 0 mm [Q1 0, Q3 1.5]; P = 0.001) and change in midline shift (median 3 mm [Q1 0, Q3 9.5] vs. median 0.5 mm [Q1 0, Q3 1.5]; P = 0.018). The thrombocytopenia cohort had higher in-hospital mortality (10 [52.6%] vs. 2 [10.5%]; P = 0.003). No significant differences were found in postoperative Glasgow Coma Scale score, length of stay, number of readmissions, and number of reoperations. CONCLUSIONS: Thrombocytopenia is significantly associated with expansion of hematoma preoperatively in patients with acute subdural hematoma. While the benefit of early platelet correction cannot be determined from this study, patients who present with thrombocytopenia will benefit from close monitoring, a low threshold to obtain repeat imaging, and anticipating early surgical evacuation after platelet optimization.

Interdisciplinary Ethics Certificate Program for Graduate Medical Education Trainees.

BACKGROUND: Ethics education is an essential component of developing physician competency and professionalism. Although prior studies have shown both a wide interest and a need for ethics education during residency, structured learning opportunities are not widely available at the graduate medical education (GME) level. OBJECTIVE: Through the Vanderbilt Center for Biomedical Ethics and Society, we developed a 1-year certificate program offering a Distinction in Biomedical Ethics, open to all active trainees in GME programs at the Vanderbilt University Medical Center. This certificate program provides advanced education in biomedical ethics and can be completed without additional cost to the trainee or time away from training. METHODS: This certificate program has been offered each academic year since 2017-2018. The program curriculum includes case-based seminars, a rotation on the Ethics Consultation Service, participation on the hospital ethics committee, and a capstone project. Outcomes were assessed using a post-course evaluation. RESULTS: During the first 4 years of the program, 65 trainees participated from 19 different specialties. Course evaluations were obtained from 58 participants (89.4% response rate) and were strongly favorable in most domains. All participants agreed that this program enhanced their knowledge of biomedical ethics and they would use something they learned in their future practice. Most participants (57 of 58, 98.3%) would recommend this course to a friend. CONCLUSIONS: We designed and implemented a Distinction in Biomedical Ethics program to provide advanced training in clinical Bioethics, which has been favorably received by participants.

Unusual presentation of empyema necessitans: case report and review of the literature.

Empyema necessitans is characterized by the extension of a pleural empyema into adjacent structures beyond the pleural space. Although rare, it adds significant complications to patients already suffering from pleural empyema. Standard of surgical care has yet to be characterized or described in the literature. Here, we describe the unusual presentation of a 55-year-old man with methicillin-sensitive Staphylococcus aureus empyema necessitans and outline both our surgical intervention and thoracic reconstruction. We present our case's presentation, management, and outcome. We then review the literature and describe a multidisciplinary approach for management. Empyema necessitans is a very rare and morbid condition requiring urgent intervention to promote optimal outcomes.

A Solution to Antifolate Resistance in Group B Streptococcus: Untargeted Metabolomics Identifies Human Milk Oligosaccharide-Induced Perturbations That Result in Potentiation of Trimethoprim.

Adjuvants can be used to potentiate the function of antibiotics whose efficacy has been reduced by acquired or intrinsic resistance. In the present study, we discovered that human milk oligosaccharides (HMOs) sensitize strains of group B Streptococcus (GBS) to trimethoprim (TMP), an antibiotic to which GBS is intrinsically resistant. Reductions in the MIC of TMP reached as high as 512-fold across a diverse panel of isolates. To better understand HMOs' mechanism of action, we characterized the metabolic response of GBS to HMO treatment using ultrahigh-performance liquid chromatography-high-resolution tandem mass spectrometry (UPLC-HRMS/MS) analysis. These data showed that when challenged by HMOs, GBS undergoes significant perturbations in metabolic pathways related to the biosynthesis and incorporation of macromolecules involved in membrane construction. This study represents reports the metabolic characterization of a cell that is perturbed by HMOs.IMPORTANCE Group B Streptococcus is an important human pathogen that causes serious infections during pregnancy which can lead to chorioamnionitis, funisitis, premature rupture of gestational membranes, preterm birth, neonatal sepsis, and death. GBS is evolving antimicrobial resistance mechanisms, and the work presented in this paper provides evidence that prebiotics such as human milk oligosaccharides can act as adjuvants to restore the utility of antibiotics.

Interrogation of Human Milk Oligosaccharide Fucosylation Patterns for Antimicrobial and Antibiofilm Trends in Group B Streptococcus.

For newborns, human milk oligosaccharides (HMOs) serve as an important source of protection against bacterial pathogens. HMOs  prevent infection by functioning as decoy receptors that bind pathogens to inhibit cellular adhesion. HMOs also play a protective role by acting as prebiotics that selectively promote the growth of symbiotic gut bacteria over pathogens. Fucosylated HMOs in particular are well-known for their roles as both decoy receptors and prebiotics. Recently, we discovered that HMOs possess antimicrobial activity against Group B Streptococcus (GBS) by increasing cellular permeability. HMO extracts from a single donor can contain over 100 different structures; however, studies using heterogeneous HMO mixtures do not provide insight into the specific structural requirements needed to achieve antimicrobial activity. In this study, we address this void by completing a structure activity study on the antimicrobial and antibiofilm activities of six neutral, fucosylated and five neutral, nonfucosylated HMOs against GBS. We determined that while the presence of fucose alone does not correlate to antimicrobial activity, the location and degree of fucosylation does play a key role in the antimicrobial activity of HMOs. Moreover, the antimicrobial and antibiofilm activities of single HMOs were found to be strain-specific. This further supports our vision of developing narrow-spectrum antibacterial agents against GBS.