Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity.

Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.

Synthetic lethality: targeting the SMARCA2 bromodomain for degradation in SMARCA4-deficient tumors - a review of patent literature from 2019-June 2023.

INTRODUCTION: SMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer. AREAS COVERED: The current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated. EXPERT OPINION: SMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.

Trends of female authorship in head and neck surgery publications over the last decade.

BACKGROUND: While other otolaryngology subspecialties have established female authorship trends, there is no comprehensive study within head and neck surgery (HNS). METHODS: Five researchers recorded the gender identity of first and senior authors from HNS subspecialty papers (head and neck oncology, endocrine surgery, salivary gland pathology, and microsurgery) derived from 10 journals in otolaryngology and oncology in the years 2013, 2016, 2019, and 2022. RESULTS: From 3457 articles, 6901 unique author identities were analyzed. Female authors represented 32% (N = 1103) of first authors and 20% (N = 690) of senior authors. Female authors were less likely to publish in microvascular and reconstructive surgery. Senior female authors were more likely to publish in higher impact journals than male senior authors, and first female authors had an increased likelihood of funding compared to their male counterparts. CONCLUSIONS: While female authors remain underrepresented in certain literature, we illustrate promising trends in productivity, funding allocation, and impact.

Adverse events associated with Vibrant Soundbridge: A MAUDE study.

OBJECTIVE: To summarize adverse events and their root causes reported to the United States Food and Drug Administration (FDA) on Vibrant Soundbridge (VSB) hearing device (Med-El, Innsbruck, Austria), an active middle ear implant for patients with moderate to severe hearing loss. MATERIALS AND METHODS: The FDA's Manufacturer and User Facility Device Experience (MAUDE) database was queried for reports of VSB adverse events from January 1, 2012, to July 27, 2022. RESULTS: Six hundred sixty-three total medical device reports were identified, from which 913 adverse events were extracted. Of these, 498 (54.5 %) were adverse events to patients (AEPs), while 415 (45.5 %) were device malfunctions (DMs). The most common AEPs were hearing performance issues 428 (85.9 %). The most common DMs were compromised conductive link 125 (30.1 %). Root causes identified for DMs were iatrogenic 85 (58.6 %), patient-related 28 (19.3 %), and trauma and external causes 32 (22.1 %). The most common iatrogenic root cause 12 (14.1 %) involved damage to the conductive link during revision surgery. The most common patient-related causes of DMs were excessive middle ear tissue growth 16 (57 %), and abrupt body movements 5 (28.6 %). The most common external cause of DM was cleaning of the ear canal or mastoid cavity 20 (62.5 %). CONCLUSIONS: Despite its well-known limitations, the MAUDE database provides valuable information on possible complications of VSB as it relates to device malfunction or adverse events for patients. Implementation of standardized reports with relevant and well-defined categories could certainly allow for a more meaningful analysis.

Synthetic lethality: targeting SMARCA2 ATPase in SMARCA4-deficient tumors - a review of patent literature from 2019-30 June 2023.

INTRODUCTION: The multi-subunit SWI/SNF chromatin remodeling complex is a key epigenetic regulator for many cellular processes, and several subunits are found to be mutated in human cancers. The inactivating mutations of SMARCA4, the ATPase subunit of the complex, result in cellular dependency on the paralog SMARCA2 for survival. This observed synthetic lethal relationship posits targeting SMARCA2 in SMARCA4-deficient settings as an attractive therapeutic target in oncology. AREAS COVERED: This review covers patent literature disclosed during the 2019-30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4. A total of 16 documents from 6 applicants are presented. EXPERT OPINION: The demonstration of cellular dependence on SMARCA2 ATPase activity in SMARCA4-deficient settings has prompted substantial research toward SMARCA2-targeting therapies. Although selectively targeting the ATPase domain of SMARCA2 is viewed as challenging, several ATPase inhibitor scaffolds have been disclosed within the last five years. Most early compounds are weakly selective, but these efforts have culminated in the first dual SMARCA2/SMARCA4 ATPase inhibitor to enter clinical trials. Data from the ongoing clinical trials, as well as continued advancement of SMARCA2-selective ATPase inhibitors, are anticipated to significantly impact the field of therapies, targeting SMARCA4-deficient tumors.

The utility of ultrasonographic surveillance in management of a presumed branchial cleft cyst later confirmed HPV-associated oropharyngeal cancer.

While branchial cleft cysts are often considered benign pathologies, the literature discusses cases of squamous cell carcinoma (SCC) arising from these cystic lesions as either a primary or metastatic tumor. We illustrate our institutional experience and review the current literature to identify recommendations for best diagnostic, surveillance, and treatment guidelines for SCC identified in a branchial cleft cyst. A 61-year-old male presented with a right sided neck mass, with suspicion of a branchial cleft cyst due to benign findings on fine needle aspiration. Following surgical excision, a focus of SCC was found on surgical pathology. Despite PET/CT and flexible laryngoscopy, no primary tumor was identified prompting routine surveillance every 3 months with cervical ultrasonography and flexible nasolaryngoscopy. Two and a half years following his initial presentation, pathologic right level II lymphadenopathy was detected on ultrasound without evidence of primary tumor. Subsequent transoral robotic surgery with right tonsillectomy and partial pharyngectomy, with right lateral neck dissection revealed a diagnosis of pT1N1 HPV-HNSCC and he was referred for adjuvant chemotherapy and radiation. To our knowledge there are less than 10 cases of confirmed HPV-associated oropharyngeal SCC arising from a branchial cleft cyst. Here we demonstrate the utility of ultrasound as a surveillance tool and emphasize a higher index of suspicion for carcinoma in adult patients with cystic neck masses.

Race and Ethnicity Independently Predict Adverse Outcomes Following Head and Neck Autograft Surgery.

OBJECTIVE: There is growing attention toward the implications of race and ethnicity on health disparities within otolaryngology. While race is an established predictor of adverse head and neck oncologic outcomes, there is paucity in the literature on studies employing national, multi-institutional data to assess the impact of race and ethnicity on head and neck autograft surgery. METHODS: Using the National Surgical Quality Improvement Program (NSQIP) database, trends in 30 days outcomes were assessed. Patients with ICD-10 codes for malignant head and neck neoplasms were isolated. Autograft surgeries were selected using Current Procedural Terminology (CPT) codes for free flap and pedicled flap reconstruction. Primary outcomes included surgical complications, reoperation, readmission, extended length of stay and operation time. Each binary categorical variable was compared to racial/ethnic identity via binary logistic regression. RESULTS: The study cohort consisted of 2447 patients who underwent head and neck autograft surgery (80.71% free flap reconstruction and 19.39% pedicled flap reconstruction). Black patients had significantly higher odds of overall surgical complications (odds ratio [OR] 1.583, 95% confidence interval [CI] 1.091, 2.298, p = 0.016) with much higher odds of perioperative blood transfusions (OR 2.291, 95% CI 1.532, 3.426, p = <.001). Hispanic patients were more likely to undergo reoperation within 30 days after surgery and were more likely to be hospitalized for more than 30 days post-operatively (OR 1.566, 95% CI 1.015, 2.418, p = 0.043 and OR 12.224, 95% CI 2.698, 55.377, p = 0.001, respectively). CONCLUSIONS: Race and ethnicity serve as independent predictors of complications in the post-operative period following head and neck autograft surgery. LEVEL OF EVIDENCE: III Laryngoscope, 2024.

Epigenetic Reprogramming Drives Epithelial Disruption in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1. Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2'-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.

Factors Influencing Underrepresented Medical Students' Career Choice in Surgical Subspecialties.

OBJECTIVES: Surgical subspecialties rank among the least racially and gender diverse of the medical specialties. The purpose of this systematic review is to evaluate the current factors that influence female, gender and sexual minority (GSM), and underrepresented in medicine (URiM)-identifying medical students' decision to pursue a career in a surgical subspecialty. DATA SOURCES: A structured literature search of PubMed, Scopus, Web of Science, and Medline was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Criteria for eligibility included surveys and interviews assessing factors and barriers influencing underrepresented medical students' career choices. REVIEW METHODS: Two independent researchers screened the articles' titles and abstracts for relevance; three performed full-text reviews. RESULTS: Of 343 studies identified, 17 met the inclusion criteria. Fourteen (82%) were survey-based studies; three (18%) were qualitative interviews. Represented minorities included females (14), URiM (13), and GSM (4). Female medical students were most influenced by (1) exposure to surgery, (2) mentorship, and (3) surgical lifestyle. URiM medical students were most influenced by (1) mentorship, (2) culture and diversity, (3) research opportunities, and (4) personality fit. GSM medical students were most influenced by identity acceptance and instances of discrimination and bias. CONCLUSIONS: Our review provides granular data on positive and negative factors influencing career choice among underrepresented medical students to facilitate the development of a more diverse surgical workforce. Female medical students were more positively influenced by increased exposure to surgical subspecialties, whereas URiM medical students were more positively influenced by race-concordant mentorship. Laryngoscope, 134:1498-1506, 2024.

Dealing with Zeros: Adolescent Drug Use, Perceived Disapproval, and Perceived Harm.

Because studies examining youth drug use often have data with a high proportion of zeros, they often do not meet the assumptions for univariate or linear regression analyses that are typically used. We demonstrate the use of zero-inflated negative binomial regression models to address excessive zeros in drug use frequency on perceptions of disapproval and perceived harm among middle and high school students (N = 522). We found that perceptions of parent disapproval were a better predictor of marijuana use (p = .01) than peer disapproval. Perceived harm was related to marijuana use (p = .04). Researchers should consider using zero-inflated negative binomial regression models when examining youth drug use.

Complications Associated with Microdebriders in Otolaryngology Procedures from 2011 to 2021: A MAUDE Study.

Objective: The microdebrider is a powered surgical instrument that is widely used in the field of otolaryngology. We aim to identify the type and frequency of device malfunctions, patient complications, and subsequent interventions related to the use of microdebriders. Study Design: Cross-sectional analysis. Setting: The US Food and Drug Administration (FDA) 2011 to 2021 Manufacturer and User Facility Device Experience (MAUDE) database. Methods: The MAUDE database was queried for reports of "microdebrider," with adverse events selected that pertained to usage in head and neck surgeries from January 1, 2011 to December 31, 2021. Results: There were 282 adverse events in 267 individual medical device reports (MDR). Although the majority of the reports did not specify the specific operation, endoscopic sinus surgery was the most common reported procedure (89, 33.3%). The most common cause of device malfunction was due to a broken piece (120, 48.2%) followed by overheating of the microdebrider motor (78, 31.3%). Of the reports which specified patient injury, the most commonly reported was "unintentional tissue damage," (10, 32.3%). Conclusion: The microdebrider has demonstrated utility within the field of otolaryngology, but is not without risk of malfunction that can cause patient injury. By understanding possible risks of microdebrider usage, including tissue damage, burns, and bleeds caused by device malfunction or operator error, physicians can be better prepared to address complications and educate patients.

Ocular Crystal-Storing Histiocytosis with Co-existing MALT Lymphoma-A Rare Case with Cytologic and Heretofore Not Reported Findings on Frozen Section.

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare disorder which most commonly occurs in the setting of concurrent lymphoproliferative disease. Morphologically, it consists of aggregates of histiocytes containing eosinophilic crystalline material, which in most cases is composed of aggregated abnormal light chains. METHODS: Using histomorphology, immunohistochemistry and in situ hybridization, the authors characterize a rare case of orbital CSH associated with extranodal marginal zone (MALT) lymphoma and report for the first time the frozen section features of CSH. RESULTS: The frozen section featured plump histiocytes with ample weakly basophilic to grayish cytoplasm with a microvacuolated appearance and focal stippling. These features stand in contrast with the formalin-fixed, paraffin embedded histomorphological appearance of aggregates of plump histiocytes with densely eosinophilic crystalline cytoplasmic material. CONCLUSION: CSH is a challenging diagnosis to make on frozen section. The artifacts that preclude its recognition, as well as differential diagnoses of this entity in the head and neck are discussed.

Risk of Local Recurrence in Men With Penile Intraepithelial Neoplasia in the Surgical Margin After Penile-sparing Surgery.

PURPOSE: Up to 90% of men with a positive surgical margin show remaining cancer in subsequent reresections. The risk of local recurrence in men with no penile cancer but the precancerous lesion penile intraepithelial neoplasia at the surgical margin is less well studied and was the aim of this analysis. MATERIAL AND METHODS: This was a retrospective analysis of men with distal penile cancer undergoing penile-sparing surgery. A competing risks survival analysis adjusted for grade, lymphovascular invasion, and stage was performed to assess local recurrence-free survival in patients with penile intraepithelial neoplasia-positive margins and completely negative surgical margins. RESULTS: A negative surgical margin was described in 319 men (85%), whereas penile intraepithelial neoplasia in the surgical margin was found in 59 men (15%). Local recurrence was observed in 30/319 men with a negative surgical margin compared to 11/59 men with penile intraepithelial neoplasia in the surgical margin. Adjusted for T stage and grade, patients with penile intraepithelial neoplasia at the surgical margin had a higher risk to develop a local recurrence than those with a negative surgical margin without penile intraepithelial neoplasia (HR 1.51, 95% CI 1.07-2.12, P = .019). CONCLUSIONS: Men with a penile intraepithelial neoplasia-positive surgical margin have an increased risk to experience local recurrence compared to men with a negative surgical margin and should undergo closer surveillance and/or adjuvant treatment.

Upregulation of the NKG2D ligand ULBP2 by JC polyomavirus infection promotes immune recognition by natural killer cells.

BACKGROUND: JC polyomavirus(JCPyV) causes progressive multifocal leukoencephalopathy(PML), a potentially fatal complication of severe immune suppression with no effective treatment. Natural killer (NK) cells play critical roles in defense against viral infections, yet NK cell response to JCPyV infection remains unexplored. METHODS: NK and T cell responses against the JCPyV VP1 were compared using intracellular cytokine staining (ICS) upon stimulation with peptide pools. A novel flow cytometry-based assay was developed to determine NK cell killing efficiency of JCPyV-infected astrocyte-derived SVG-A cells. Blocking antibodies were used to identify the specific NK cell receptors in immune recognition of JCPyV-infected cells. RESULTS: In about 40% of healthy donors, we detected robust CD107a upregulation and IFN-γ production by NK cells, extending beyond T cell responses. Next, using the NK cell-mediated killing assay, we showed that co-culture of NK cells and JCPyV-infected SVG-A cells leads to a 60% reduction in infection, on average. JCPyV-infected cells had enhanced expression of ULBP2 - a ligand for the activating NK cell receptor NKG2D and addition of NKG2D blocking antibodies decreased NK cell degranulation. CONCLUSION: NKG2D-mediated activation of NK cells plays a key role in controlling JCPyV replication and may be a promising immunotherapeutic target to boost NK cell anti-JCPyV activity.

Spare the Nipple: A Systematic Review of Tumor Nipple-Distance and Oncologic Outcomes in Nipple-Sparing Mastectomy.

BACKGROUND: Preserving the nipple-areolar complex (NAC) in breast cancer surgery improves patient satisfaction and quality of life. The oncologic safety of NSM in tumors < 2 cm from the nipple remains in question. We conducted a systematic review to determine whether TND < 2 cm was associated with increased risk of LRR in patients undergoing NSM. METHODS: We included studies of invasive or in situ breast cancer < 2 cm from NAC undergoing NSM which reported LRR rates. LRR rates were stratified by TND and culminated across studies. Cohort study quality was assessed using Newcastle-Ottawa Criteria. Meta-analysis was not possible due to heterogeneity in reporting survival outcomes. RESULTS: We identified seven retrospective cohort studies with 2295 patients and 18 case series with 3507 patients. Direct tumor involvement of NAC was considered an absolute contraindication to NSM in all studies. In cohort studies, median follow-up was 31-112 (range 14-204) months. Cohorts with TND < 2 cm did not have a significantly higher rate of LRR. Amongst case series, 275 patients had TND < 2 cm. Combined LRR in case series was 2.6%, with median follow-up 10.4-71 (range 0-158) months. CONCLUSIONS: Our systematic review did not identify TND < 2 cm as a significant risk factor for LRR. NSM appears oncologically safe in select patients with TND < 2 cm. Given the improved quality of life associated with NSM compared to skin-sparing mastectomy, we suggest NSM as the procedure of choice in appropriately selected patients.

SARS-CoV-2 infection alters mitochondrial and cytoskeletal function in human respiratory epithelial cells mediated by expression of spike protein.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, SCV2), which has resulted in higher morbidity and mortality rate than other respiratory viral infections, such as Influenza A virus (IAV) infection. Investigating the molecular mechanisms of SCV2-host infection vs IAV is vital in exploring antiviral drug targets against SCV2. We assessed differential gene expression in human nasal cells upon SCV2 or IAV infection using RNA sequencing. Compared to IAV, we observed alterations in both metabolic and cytoskeletal pathways suggestive of epithelial remodeling in the SCV2-infected cells, reminiscent of pathways activated as a response to chronic injury. We found that spike protein interaction with the epithelium was sufficient to instigate these epithelial responses using a SCV2 spike pseudovirus. Specifically, we found downregulation of the mitochondrial markers SIRT3 and TOMM22. Moreover, SCV2 spike infection increased extracellular acidification and decreased oxygen consumption rate in the epithelium. In addition, we observed cytoskeletal rearrangements with a reduction in the actin-severing protein cofilin-1 and an increase in polymerized actin, indicating epithelial cytoskeletal rearrangements. This study revealed distinct epithelial responses to SCV2 infection, with early mitochondrial dysfunction in the host cells and evidence of cytoskeletal remodeling that could contribute to the worsened outcome in COVID-19 patients compared to IAV patients. These changes in cell structure and energetics could contribute to cellular resilience early during infection, allowing for prolonged cell survival and potentially paving the way for more chronic symptoms. IMPORTANCE COVID-19 has caused a global pandemic affecting millions of people worldwide, resulting in a higher mortality rate and concerns of more persistent symptoms compared to influenza A. To study this, we compare lung epithelial responses to both viruses. Interestingly, we found that in response to SARS-CoV-2 infection, the cellular energetics changed and there were cell structural rearrangements. These changes in cell structure could lead to prolonged epithelial cell survival, even in the face of not working well, potentially contributing to the development of chronic symptoms. In summary, these findings represent strategies utilized by the cell to survive the infection but result in a fundamental shift in the epithelial phenotype, with potential long-term consequences, which could set the stage for the development of chronic lung disease or long COVID-19.

Adipose Tissue-Derived Mesenchymal Stem Cell-Derived Exosomes Promote Wound Healing and Tissue Regeneration.

Wound healing is a complex process involving cell proliferation, migration, and extracellular matrix (ECM) remodeling. Extracellular vesicles (EVs) or exosomes derived from adipose tissue-derived stem cells (ASCs) are emerging as promising alternatives to cell therapy for advanced wound healing. Hyaluronic acid (HA), a major component of the skin ECM, is widely utilized in wound dressings and dermal fillers. This study aimed to investigate the effects of ASC-derived exosomes (ASC-EXOs) on human dermal fibroblasts (HDFs) and their potential combination with HA in in vivo wound healing and dermal filler models. In HDFs, ASC-EXOs increased cell proliferation and migration. ASC-EXOs also upregulated the expression of genes involved in cell proliferation and wound healing while stimulating collagen production in HDFs. In a porcine wound healing model, topical treatment with a combination of HA and ASC-EXOs led to higher wound closure rates compared to HA alone. Histological examination showed increased re-epithelialization and collagen type III deposition in wounds treated with the combination of HA and ASC-EXOs. In a mouse dermal filler model, tissues injected with the combination of HA and ASC-EXOs exhibited thicker tissue layers, increased vascularization, enhanced infiltration of myofibroblasts, and higher levels of collagen III and collagen fiber content compared to HA alone. These findings suggest that ASC-EXOs have beneficial effects on cell proliferation, migration, and gene expression related to wound healing, and they may accelerate wound closure and promote tissue regeneration. Furthermore, the combination of HA and ASC-EXOs may enhance wound healing and tissue remodeling, indicating its potential for both clinical and regenerative aesthetic applications in skin repair and regeneration.

Timeliness of Multimodal Care for At-Risk Breast Cancer Patients at a Safety Net Institution.

INTRODUCTION: Because limited data exist, we sought to evaluate timeliness of multimodal treatments in a safety net breast cancer population. METHODS: Breast cancer patients treated at a safety net hospital from 2016 to 2020 were analyzed retrospectively. Time intervals were defined as primary time (PT) from diagnosis to initiation of primary intervention, secondary time (ST) from completion of primary to initiation of secondary intervention, and tertiary time (TT) from completion of secondary to initiation of tertiary intervention. Variables included primary language, insurance type, and race. RESULTS: Of 223 patients, 99 (44.4%) primarily spoke Spanish, 29 (13.0%) were of Black race, and 184 (82.5%) had Medicaid or uninsured status. Median (IQR) age at diagnosis was 55 (48-62) years. Primary intervention was surgical in 127/216 (58.8%); secondary intervention was systemic in 38/169 (22.5%); and tertiary intervention was radiation in 67/80 (83.8%). Overall, median days (IQR) for PT were 69 (53, 98), ST were 65 (42, 95), and TT were 69 (43, 88). PT was significantly longer in Black [105 (76, 142) days] patients compared to non-Hispanic White patients [68 (51, 107) days, P = 0.031)] and White Hispanic patients [65 (53,91) days, P = 0.014]. There were no significant differences in PT, ST, or TT by spoken language or insurance type. CONCLUSIONS: Black patients remain at risk due to prolonged time to intervention. Spanish-speaking status was not associated with inferior timeliness or completion of multimodal care at a safety net hospital. Identifying safety net hospital barriers to achieving benchmarks for timely completion of all phases of multimodal care warrants further attention.

A transient flow reactor for rapid gas switching at atmospheric pressure.

Herein, we present a design for a transient flow reactor system with high detection sensitivity and minimal dead volume, such that it is capable of sub-second switching of the gas stream flowing through a catalytic bed. We demonstrate the reactor's capabilities for step transient, pulse, and stream oscillation experiments using the model system of CO oxidation over Pd catalysts, and we find that we are able to precisely model step transients for CO oxidation using a pseudo-homogenous-packed bed reactor model. The design principles leading to minimal gas hold-up time and increased sensitivity that are described in this paper can be implemented into existing flow reactor designs with minimal cost, providing a readily accessible alternative to the existing transient instrumentation.