Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:Abdominal pain is a major symptom of diseases that are associated with microbial dysbiosis, including irritable bowel syndrome and inflammatory bowel disease. Germ-free mice are more prone to abdominal pain than conventionally housed mice, and reconstitution of the microbiota in germ-free mice reduces abdominal pain sensitivity. However, the mechanisms underlying microbial modulation of pain remain elusive. We hypothesized that disruption of the intestinal microbiota modulates the excitability of peripheral nociceptive neurons. METHODS:In vivo and in vitro assays of visceral sensation were performed on mice treated with the nonabsorbable antibiotic vancomycin (50 μg/mL in drinking water) for 7 days and water-treated control mice. Bacterial dysbiosis was verified by 16s rRNA analysis of stool microbial composition. RESULTS:Treatment of mice with vancomycin led to an increased sensitivity to colonic distension in vivo and in vitro and hyperexcitability of dorsal root ganglion (DRG) neurons in vitro, compared with controls. Interestingly, hyperexcitability of DRG neurons was not restricted to those that innervated the gut, suggesting a widespread effect of gut dysbiosis on peripheral pain circuits. Consistent with this, mice treated with vancomycin were more sensitive than control mice to thermal stimuli applied to hind paws. Incubation of DRG neurons from naive mice in serum from vancomycin-treated mice increased DRG neuron excitability, suggesting that microbial dysbiosis alters circulating mediators that influence nociception. The cysteine protease inhibitor E64 (30 nmol/L) and the protease-activated receptor 2 (PAR-2) antagonist GB-83 (10 μmol/L) each blocked the increase in DRG neuron excitability in response to serum from vancomycin-treated mice, as did the knockout of PAR-2 in NaV1.8-expressing neurons. Stool supernatant, but not colonic supernatant, from mice treated with vancomycin increased DRG neuron excitability via cysteine protease activation of PAR-2. CONCLUSIONS:Together, these data suggest that gut microbial dysbiosis alters pain sensitivity and identify cysteine proteases as a potential mediator of this effect.

Hearing loss is common among Veterans, and extensive hearing care resources are prioritized within the Veterans Administration (VA). Severe hearing loss poses unique communication challenges with speech understanding that may not be overcome with amplification. We analyzed data from the VA Audiometric Repository between 2005 and 2017 and the relationship between hearing loss severity with speech recognition scores. We hypothesized that a significant subset of Veterans with severe or worse hearing loss would have poor unaided speech perception outcomes even with adequate audibility. Sociodemographic characteristics and comorbidities were compiled using electronic medical records as was self-report measures of hearing disability. We identified a cohort of 137,500 unique Veterans with 232,789 audiograms demonstrating bilateral severe or worse hearing loss (four-frequency PTA > 70 dB HL). The median (IQR; range) age of Veterans at their first audiogram with severe or worse hearing loss was 81 years (74 to 87; 21-90+), and a majority were male (136,087 [99%]) and non-Hispanic white (107,798 [78.4%]). Among those with bilateral severe or worse hearing loss, 41,901 (30.5%) also had poor speech recognition scores (<50% words), with greater hearing loss severity correlating with worse speech perception. We observed variability in speech perception abilities in those with moderate-severe and greater levels of hearing loss who may derive limited benefit from amplification. Veterans with communication challenges may warrant alternative approaches and treatment strategies such as cochlear implants to support communication needs.

The most widely used fluorophore in glioma-resection surgery, 5-aminolevulinic acid (5-ALA), is thought to cause the selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumour cells. Here we show that the clinical detection of PpIX can be improved via a microscope that performs paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF). We validated the technique in fresh tumour specimens from 115 patients with high-grade gliomas across four medical institutions. We found a weak negative correlation between tissue cellularity and the fluorescence intensity of PpIX across all imaged specimens. Semi-supervised clustering of the TPEF images revealed five distinct patterns of PpIX fluorescence, and spatial transcriptomic analyses of the imaged tissue showed that myeloid cells predominate in areas where PpIX accumulates in the intracellular space. Further analysis of external spatially resolved metabolomics, transcriptomics and RNA-sequencing datasets from glioblastoma specimens confirmed that myeloid cells preferentially accumulate and metabolize PpIX. Our findings question 5-ALA-induced fluorescence in glioma cells and show how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of gliomas.

Evidence on facial rehabilitation therapy (FRT) for acute facial paralysis (FP) remains limited. We present a retrospective review of patients with acute FP who have received FRT with physical therapists within 1 year of FP onset as determined by Sunnybrook Facial Grading Scale (SFGS) composite scores. A total of 702 patients with a clinical diagnosis of FP were referred to a university rehabilitation program between January 1, 2015 and January 1, 2022. Seventy-six patients met the criteria, defined as FP diagnosis <12 months before FRT initiation, ≥3 therapy sessions, and sufficient follow-up data. Average number of treatment sessions between SFGS scores was 7.7. History of cancer, sex, number of treatment sessions, and initial SFGS score were correlated with change in SFGS. Time to treatment was not correlated with change in SFGS score. SFGS improved with each additional treatment session (p < 0.01). Each additional point in the initial SFGS was correlated with less change in the final SFGS score (p < 0.01). FRT can provide meaningful improvement in functionality for patients with acute FP, regardless of time to treatment. Furthermore, patients who present with poorer functionality at baseline and those who undergo more treatment are most likely to see SFGS improvement. Research comparing the effect of facial rehabilitation with other treatment modalities and to a control cohort is warranted.

OBJECTIVE:To better understand cochlear implant (CI) performance after reimplantation with a different device manufacturer. STUDY DESIGN/METHODS:Multisite retrospective review. SETTING/METHODS:Tertiary referral centers. PATIENTS/METHODS:Patients older than 4 years who received a CI and subsequently underwent CI reimplantation with a different manufacturer over a 20-year period. INTERVENTION/METHODS:Reimplantation. MAIN OUTCOME MEASURE/METHODS:The primary outcome was difference in the best CNC score obtained with the primary CI, compared with the most recent CNC score obtained after reimplantation. RESULTS:Twenty-nine patients met the criteria at three centers. The best average CNC score achieved by adult patients after primary cochlear implantation was 46.2% (n = 16), measured an average of 14 months (range: 3-36 mo) postoperatively. When looking at the most recent CNC score of adult patients before undergoing reimplantation, the average CNC score dropped to 19.2% (n = 17). After reimplantation, the average 3- to 6-month CNC score was 48.3% (n = 12), with most recent average CNC score being 44.4% (n = 17) measured an average of 19 months (range: 3-46 mo) postoperatively. There was no statistically significant difference (p = 0.321; t11 = 0.48) identified in performance between the best CNC score achieved by adult patients after primary cochlear implantation, and the most recent score achieved after reimplantation (n = 12). Analysis of prerevision and postrevision speech performance was not possible in pediatric patients (<18 yr old) because of differences in tests administered. CONCLUSION/CONCLUSIONS:Patients undergoing reimplantation with a different manufacturer achieved CNC score performance comparable to their best performance with their original device.

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8⁺ T cells and exhausted CD8⁺ T cell (T_EX) clones. Focused analyses of T_EX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T_EX, which synergizes with anti-PD-1 to reinvigorate T_EX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

OBJECTIVE:To characterize transimpedance matrix (TIM) heatmap patterns in patients at risk of labyrinthine abnormality to better understand accuracy and possible TIM limitations. STUDY DESIGN/METHODS:Retrospective review of TIM patterns, preoperative, and postoperative imaging. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Patients undergoing cochlear implantation with risk of labyrinthine abnormality. INTERVENTION/METHODS:None. RESULTS:Seventy-seven patients were evaluated. Twenty-five percent (n = 19) of patients had a TIM pattern variant identified. These variants were separated into 10 novel categories. Overall, 9% (n = 6) of electrodes were malpositioned on intraoperative x-ray, of which 50% (n = 3) were underinserted, 17% (n = 1) were overinserted, 17% (n = 1) had a tip foldover, and 17% (n = 1) had a coiled electrode. The number of patients with a variant TIM pattern and normal x-ray was 18% (n = 14), and the number of patients with normal TIM pattern and malposition noted on x-ray was 3% (n = 2; both were electrode underinsertions that were recognized due to open circuits and surgical visualization).A newly defined skip heat pattern was identified in patients with IP2/Mondini malformation and interscalar septum width <0.5 mm at the cochlear pars ascendens of the basal turn. CONCLUSIONS:This study defines novel patterns for TIM heatmap characterization to facilitate collaborative and comparative research moving forward. In doing so, it highlights a new pattern termed skip heat, which corresponds with a deficient interscalar septum of the cochlea pars ascendens of the basal turn in patients with IP2 malformation. Overall, the data assist the surgeon in better understanding the implications and limitations of TIM patterns within groups of patients with risk of labyrinthine abnormalities.

BACKGROUND/UNASSIGNED:In many cancers, specific subtypes are more prevalent in specific racial backgrounds. However, little is known about the racial distribution of specific molecular types of brain tumors. Public data repositories lack data on many brain tumor subtypes as well as diagnostic annotation using the current World Health Organization classification. A better understanding of the prevalence of brain tumors in different racial backgrounds may provide insight into tumor predisposition and development, and improve prevention. METHODS/UNASSIGNED:We retrospectively analyzed the racial distribution of 1709 primary brain tumors classified by their methylation profiles using clinically validated whole genome DNA methylation. Self-reported race was obtained from medical records. Our cohort included 82% White, 10% Black, and 8% Asian patients with 74% of patients reporting their race. RESULTS/UNASSIGNED: < .001). CONCLUSIONS/UNASSIGNED:Molecularly classified brain tumor groups and subgroups show different distributions among the three main racial backgrounds suggesting the contribution of race to brain tumor development.

BACKGROUND:Predictors of outcomes in pediatric microtia surgery are not well understood within the current literature. A multi-institutional database study may reveal insights into these predictors. OBJECTIVES/OBJECTIVE:To explore the predictors of 30-day complications, 30-day readmission, and postoperative length of stay (PLOS) in pediatric microtia patients undergoing autologous rib grafting. METHODS:The Pediatric National Surgical Quality Improvement Program was queried for details on patients with microtia (ICD-9/10 744.23/Q17.2) who underwent autologous rib grafting (CPT 21230) between 2012-2021. Demographics, comorbidities, inpatient status, 30-day complications, PLOS, and 30-day readmissions were analyzed. Statistical analyses were performed to compare the preoperative characteristics with postoperative outcomes. RESULTS:Overall, 667 patients met the inclusion criteria. Sixty-three (9.4%) had at least one complication, and 19 (2.9%) were readmitted. Univariate analysis showed that inpatient status (p = 0.011) and race (p = 0.023) were associated with higher complication rates. Multivariate analysis revealed that outpatient status was associated with significantly lower odds of complications (OR: 0.49, 95% CI [0.27, 0.87], p = 0.018), and developmental delay was associated with higher odds of 30-day readmission (OR: 2.80, 95% CI [1.05, 7.17], p = 0.036). Longer operative time was associated with older age (13.9% increase per five-year age increase, p < 0.001) and inpatient status (35.3% increase, p < 0.001). PLOS was shorter for outpatients (45.45% shorter, p < 0.001) and cases performed by plastic surgeons (14.2% shorter, p < 0.001). CONCLUSION/CONCLUSIONS:Microtia reconstruction using autologous cartilage is a relatively safe procedure with low complication and readmission rates. Significant predictors of postoperative outcomes include inpatient status, race, developmental delay, and age. These findings highlight the importance of considering these factors in surgical planning and patient counseling.

There are many etiologies for respiratory distress in newborns, one of the rare causes being nasopharyngeal tumors. Of that category, salivary gland anlage tumor (SGAT) is exceedingly rare. Symptoms of SGAT vary by patient, but the most common presenting symptom is respiratory distress. The rarity of SGAT and infantile nasopharyngeal tumors in general can lead to delayed diagnosis in newborns with respiratory distress. We report an unexpected and incidental finding of this potentially life-threatening condition in the neonatal population. A preterm male infant with respiratory distress, who was undergoing a neurological workup for new hypotonia, was found to have an incidental nasopharyngeal mass after brain MRI. Upon eventual minimally invasive endoscopic surgical excision and pathologic workup for the mass, the patient was diagnosed with SGAT. The patient has since been with outpatient follow-up visits with no evidence of recurrence of the mass. The purpose of this report is to present a rare and often overlooked life-threatening diagnosis of respiratory distress in the neonatal population.