TCF1-LEF1 co-expression identifies a multipotent progenitor cell (TH2-MPP) across human allergic diseases.

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.

Patient Experience of Head and Neck Surgery With Free Flap Reconstruction.

Importance: Major head and neck surgery with microvascular free tissue transfer reconstruction is complex, with considerable risk of morbidity. Little is known about patients' experiences, including decision-making prior to, and regret following, free flap surgery. Objective: To characterize patient experiences and decision regret of patients undergoing head and neck reconstructive free flap surgery. Design, Setting, and Participants: This mixed-methods cohort study comprising semistructured interviews was conducted June to August 2021 at a single tertiary academic cancer center. Participants underwent head and neck reconstructive surgery with microvascular free tissue transfer (flap) more than 3 months before recruitment (range, 3 months to 4 years). Interview transcripts were qualitatively analyzed for themes. Participants also completed a Decision Regret Scale questionnaire. Exposure: Microvascular free flap surgery for head and neck reconstruction. Main Outcomes and Measures: Thematic analysis of interviews, decision regret score. Results: Seventeen participants were interviewed. Median (IQR) age was 61 (52-70) years. Overall, 7 participants were women (49%), and 10 of 17 were men (59%). The most common free flap was fibula (8/17, 47%). Three major themes with 9 subthemes were identified: theme 1 was the tremendous effect of preoperative counseling on surgical decision-making and satisfaction, with subthemes including (1) importance of clinical care team counseling on decision to have surgery; (2) emotional context colors preoperative understanding and retention of information; (3) expectation-setting affects satisfaction with preoperative counseling; and (4) desire for diversified delivery of preoperative information. Theme 2 was coexisting and often conflicting priorities, including (1) desire to survive above all else, and (2) desire for quality of life. Theme 3 was perception of surgery as momentous and distressing, including (1) surgery as a traumatic event; (2) centrality of mental health, emotional resolve, and gratitude to enduring surgery and recovery; and (3) sense of accomplishment in recovery. On the Decision Regret Scale, most participants had no regret (n = 8, 47%) or mild regret (n = 5, 29%); 4 had moderate-to-severe regret (24%). Conclusions and Relevance: In this mixed-methods cohort study, patient experiences surrounding major head and neck reconstructive free flap surgery were described. Opportunities to improve support for this complex and vulnerable population, and to mitigate decision regret, were identified.

Not just snot: Local inflammatory profiles in patients with aspirin-exacerbated respiratory disease differ from patients with aspirin-tolerant chronic rhinosinusitis.

KEY POINTS: IL-5, CCL2, and CXCL8 in sinus mucous are higher in patients with AERD relative to aspirin-tolerant patients with CRS These mediators are pleiotropic, leading to widescale inflammatory processes contributing to AERD AERD is not only a T2 disease but heterogeneous: this may explain the refractory nature of AERD.

Addressing Climate Health: A Practical Guide to Quantifying and Reducing Health Care-Associated Emissions.

OBJECTIVE: The objective was to quantify annual greenhouse gas emissions from a surgical specialty hospital and identify high-yield areas to reduce emissions associated with patient care. STUDY DESIGN: Pre-post study, greenhouse gas inventory. SETTING: Specialty hospital. METHODS: A scope 1 and scope 2 greenhouse gas inventory of the Massachusetts Eye and Ear main campus for calendar years (CY) 2020, 2021, and 2022 was performed by assessing emissions attributable to on-site sources (scope 1) and purchased electricity and steam (scope 2). The associated carbon dioxide equivalent was then calculated using known global warming potentials and emission factors. RESULTS: The major contributors to scope 1 and scope 2 emissions at our institution for CY 2020 to 2022 were waste anesthetic gases and purchased steam. These results were reviewed with hospital leadership and a plan was developed to reduce these emissions. Emission monitoring is ongoing to assess the efficacy of these interventions. CONCLUSION: Measuring scope 1 and scope 2 emissions at the facility level allows health care facilities to develop institution-specific interventions and compare data across health care organizations. Surgeons can lead on health care system sustainability by collaborating with clinical and nonclinical staff to measure emissions, developing targeted emissions-reduction interventions, and tracking progress with yearly assessments.

Barriers and Facilitators to Clinical Practice Development in Men and Women Surgeons.

Importance: Many early-career surgeons struggle to develop their clinical practices, leading to high rates of burnout and attrition. Furthermore, women in surgery receive fewer, less complex, and less remunerative referrals compared with men. An enhanced understanding of the social and structural barriers to optimal growth and equity in clinical practice development is fundamental to guiding interventions to support academic surgeons. Objective: To identify the barriers and facilitators to clinical practice development with attention to differences related to surgeon gender. Design, Setting, and Participants: A multi-institutional qualitative descriptive study was performed using semistructured interviews analyzed with a grounded theory approach. Interviews were conducted at 5 academic medical centers in the US between July 12, 2022, and January 31, 2023. Surgeons with at least 1 year of independent practice experience were selected using purposeful sampling to obtain a representative sample by gender, specialty, academic rank, and years of experience. Main Outcomes and Measures: Surgeon perspectives on external barriers and facilitators of clinical practice development and strategies to support practice development for new academic surgeons. Results: A total of 45 surgeons were interviewed (23 women [51%], 18 with ≤5 years of experience [40%], and 20 with ≥10 years of experience [44%]). Surgeons reported barriers and facilitators related to their colleagues, department, institution, and environment. Dominant themes for both genders were related to competition, case distribution among partners, resource allocation, and geographic market saturation. Women surgeons reported additional challenges related to gender-based discrimination (exclusion, questioning of expertise, role misidentification, salary disparities, and unequal resource allocation) and additional demands (related to appearance, self-advocacy, and nonoperative patient care). Gender concordance with patients and referring physicians was a facilitator of practice development for women. Surgeons suggested several strategies for their colleagues, department, and institution to improve practice development by amplifying facilitators and promoting objectivity and transparency in resource allocation and referrals. Conclusions and Relevance: The findings of this qualitative study suggest that a surgeon's external context has a substantial influence on their practice development. Academic institutions and departments of surgery may consider the influence of their structures and policies on early career surgeons to accelerate practice development and workplace equity.

Perceived Implications of Compensation Structure for Academic Surgical Practice: A Qualitative Study.

This qualitative study examines how incentive-based and salary-only compensation models affect academic surgeons.

Local cytokine levels associate with SNOT-22 and UPSIT scores in chronic rhinosinusitis.

KEY POINTS: Elevated IL-5, IL-13, IL-33, and CCL2 correlate with lower UPSIT scores in CRS and AERD patients. Elevated IL-5, IL-13, TNF-α, CCL2, and CXCL-8 correlate with higher SNOT-22 scores in CRS and AERD patients.

Personal Social Networks and Care-Seeking for Head and Neck Cancer: A Qualitative Study.

OBJECTIVES: To investigate the role of patients' personal social networks (SNs) in accessing head and neck cancer (HNC) care through patients' and health care workers' (HCWs) perspectives. STUDY DESIGN: Qualitative study. SETTING: Tertiary HNC centers at 2 academic medical centers, including 1 safety net hospital. METHODS: Patients with newly diagnosed HNC, and HCWs caring for HNC patients, aged ≥18 years were recruited between June 2022 and July 2023. Semistructured interviews were conducted with both patients and HCWs. Inductive and deductive thematic analysis was performed with 2 coders (κ = 0.82) to analyze the data. RESULTS: The study included 72 participants: 42 patients (mean age 57 years, 64% female, 81% white), and 30 HCWs (mean age 42 years, 77% female, 83% white). Four themes emerged: (1) Patients' SNs facilitate care through various forms of support, (2) patients may hesitate to seek help from their networks, (3) obligations toward SNs may act as barriers to seeking care, and (4) the SN composition and dedication influence care-seeking. CONCLUSION: Personal SNs play a vital role in prompting early care-seeking among HNC patients. SN-based interventions could enhance care and improve outcomes for HNC patients.

Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps.

Background: The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood. Objective: We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation. Methods: Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and ex vivo functional analysis of sinus EpCs were used to validate our findings. Results: Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and ex vivo inhibition demonstrated that mTOR is critical for EpC generation of CXCL8, IL-33, and CXCL2. Across patient samples, the degree of glycolytic activity was associated with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in severe asthma. Conclusions: Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.

Optimizing cryopreservation of nasal polyp tissue for cellular functional studies and single-cell RNA sequencing.

KEY POINTS: Mast cell numbers were reduced in samples cryopreserved as whole tissue chunks. Thawed epithelial cells had reduced proliferation rates when preserved as dissociated cell suspensions. The right cryopreservation method to choose may depend on the goals and cell-type focus of the project.

Environmental sustainability in otolaryngologic surgery.

PURPOSE OF REVIEW: Climate change is an urgent public health crisis that significantly impacts disease development, health outcomes, and access to care. The major approaches to climate change are mitigation and adaptation. The purpose of this review is to discuss the effects of climate change on health and health disparities, review the carbon footprint of surgical care and discuss strategies for surgeons to reduce emissions and advocate for sustainability. RECENT FINDINGS: Recent studies increasingly demonstrate the direct and indirect health effects of climate change, including the relationship between climate and otolaryngologic disease. Within the domain of otolaryngology, we summarize findings related to climate change and health and healthcare delivery; health disparities; healthcare-associated emissions; and the role of otolaryngologists in mitigating and adapting to the climate crisis. There are many recent studies that identify impactful sustainability opportunities and initiatives for healthcare providers. Climate solutions may also reduce cost and have potential clinical benefits. SUMMARY: Climate change and air pollution directly impact disease burden in otolaryngology patients and are underrecognized social determinants of health. Surgeons can lead on climate change by implementing sustainability initiatives in the operating room and engaging in research and advocacy.

Healthcare Disparities in Otolaryngology.

Purpose of Review: The purpose of this review is to summarize some of the recent research studies on healthcare disparities across various subspecialties within otolaryngology. This review also highlights the impact of COVID-19 pandemic on disparities and proposes potential interventions to mitigate disparities. Recent Findings: Significant healthcare disparities in care and treatment outcomes have been reported across all areas of otolaryngology. Notable differences in survival, disease recurrence, and overall mortality have been noted based on race, ethnicity, socioeconomic status (SES), insurance status, etc. This is most well-researched in head and neck cancer (HNC) within otolaryngology. Summary: Healthcare disparities have been identified by numerous research studies within otolaryngology for many vulnerable groups that include racial and ethnic minority groups, low-income populations, and individuals from rural areas among many others. These populations continue to experience suboptimal access to timely, quality otolaryngologic care that exacerbate disparities in health outcomes.

Association of hospital centrality in inter-hospital patient-sharing networks with patient mortality and length of stay.

OBJECTIVE: The interdependence of hospitals is underappreciated in patient outcomes studies. We used a network science approach to foreground this interdependence. Specifically, within two large state-based interhospital networks, we examined the relationship of a hospital's network position with in-hospital mortality and length of stay. METHODS: We constructed interhospital network graphs using data from the Healthcare Cost and Utilization Project and the American Hospital Association Annual Survey for Florida (2014) and California (2011). The exposure of interest was hospital centrality, defined as weighted degree (sum of all ties to a given hospital from other hospitals). The outcomes were in-hospital mortality and length of stay with sub-analyses for four acute medical conditions: pneumonia, heart failure, ischemic stroke, myocardial infarction. We compared outcomes for each quartile of hospital centrality relative to the most central quartile (Q4), independent of patient- and hospital-level characteristics, in this retrospective cross-sectional study. RESULTS: The inpatient cohorts had 1,246,169 patients in Florida and 1,415,728 in California. Compared to Florida's central hospitals which had an overall mortality 1.60%, peripheral hospitals had higher in-hospital mortality (1.97%, adjusted OR (95%CI): Q1 1.61 (1.37, 1.89), p<0.001). Hospitals in the middle quartiles had lower in-hospital mortality compared to central hospitals (%, adjusted OR (95% CI): Q2 1.39%, 0.79 (0.70, 0.89), p<0.001; Q3 1.33%, 0.78 (0.70, 0.87), p<0.001). Peripheral hospitals had longer lengths of stay (adjusted incidence rate ratio (95% CI): Q1 2.47 (2.44, 2.50), p<0.001). These findings were replicated in California, and in patients with heart failure and pneumonia in Florida. These results show a u-shaped distribution of outcomes based on hospital network centrality quartile. CONCLUSIONS: The position of hospitals within an inter-hospital network is associated with patient outcomes. Specifically, hospitals located in the peripheral or central positions may be most vulnerable to diminished quality outcomes due to the network. Results should be replicated with deeper clinical data.

Type 2 inflammation drives an airway basal stem cell program through insulin receptor substrate signaling.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. OBJECTIVE: We sought to determine the role of T2 cytokines in regulating airway BCs. METHODS: Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration. RESULTS: Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP. CONCLUSIONS: These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.

Association between Surgery, Anesthesia, and Obstetric Workforce and Emergent Surgical and Obstetric Mortality among United States Hospital Referral Regions.

OBJECTIVE: To determine the association between SAO workforce and mortality from emergent surgical and obstetric conditions within US HR Rs. BACKGROUND: SAO workforce per capita has been identified as a core metric of surgical capacity by the Lancet Commission on Global Surgery, but its utility has not been assessed at the subnational level for a high-income country. METHODS: The number of practicing surgeons, anesthesiologists, and obstetricians per capita was estimated for all HRRs using the US Health Resources & Services Administration Area Health Resource File Database. Deaths due to emergent general surgical and obstetric conditions were determined from the Center for Disease Control and Prevention WONDER database. We utilized B-spline quantile regression to model the relationship between SAO workforce and emergent surgical mortality at different quantiles of mortality and calculated the expected change in mortality associated with increases in SAO workforce. RESULTS: The median SAO workforce across all HRRs was 74.2 per 100,000 population (interquartile range 33.3-241.0). All HRRs met the Lancet Commission on Global Surgery lower target of 20 SAO per 100,000, and 97.7% met the upper target of 40 per 100,000. Nearly 2.8 million Americans lived in HRRs with fewer than 40 SAO per 100,000. Increases in SAO workforce were associated with decreases in surgical mortality in HRRs with high mortality, with minimal additional decreases in mortality above 60 to 80 SAO per 100,000. CONCLUSIONS: Increasing SAO workforce capacity may reduce emergent surgical and obstetric mortality in regions with high surgical mortality but diminishing returns may be seen above 60 to 80 SAO per 100,000. Trial Registration: N/A.

Establishing the Essential Role of Household Extenders for Surgeon Wellbeing.

OBJECTIVE: The aim of this study was to investigate the association between a change in household support during the Covid-19 pandemic and surgeon stress. BACKGROUND: The hours and unpredictability of surgical practice often necessitate the employment of household extenders (eg, child caregivers) to maintain a safe home environment for surgeons and their families. The Covid-19 pandemic destabilized these relationships and provided an opportunity to reflect on the role that household extenders play in a surgical household. METHODS: A multi-institutional telephone survey of surgeons practicing at five geographically diverse academic institutions was conducted (May 15, 2020-June 5, 2020). Surgeons were classified by change in household extenders (HE) during the pandemic (decrease, increase, no change, or none). The primary outcome was self-reported surgeon stress level. Multivariable linear regression was used to examine the relationship between change in HE and surgeon stress, adjusting for training and relationship status, the presence of pets and children in the household, and study site. RESULTS: The majority (182, 54.3%) of surgeons employed HE before the pandemic; 121 (36.1%) reported a decrease in HE during the pandemic, 9 (2.7%) reported an increase, and 52 (15.5%) reported no change. Stress scores varied significantly by change in HE group ( P = 0.016). After controlling for potential confounders, having an increase in HE was associated with a higher stress score (+1.55 points) than having no decrease in HE (P = 0.033), and having a decrease in HE was associated with a higher stress score (+0.96 points) than having no decrease ( P = 0.004). CONCLUSIONS: Household extenders play a vital and complex role in enabling the healthcare workforce to care of the population. Surgeons who experienced a change in household extenders reported the highest stress levels. We suggest that health systems should proactively support surgeons by supporting the household extender workforce.

Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects.

Background: Parenteral anti-CD3 Mab (OKT3) has been used to treat transplant rejection and parental administration of a humanized anti-CD3 Mab (Teplizumab) showed positive effects in diabetes. Nasal administration of anti-CD3 Mab has not been carried out in humans. Nasal anti-CD3 Mab suppresses autoimmune diseases and central nervous system (CNS) inflammation in animal models. We investigated the safety and immune effects of a fully humanized, previously uncharacterized nasal anti-CD3 Mab (Foralumab) in humans and its in vitro stimulatory properties. Methods: In vitro, Foralumab were compared to UCHT1 anti-human CD3 mAb. For human administration, 27 healthy volunteers (9 per group) received nasal Foralumab or placebo at a dose of 10ug, 50ug, or 250ug daily for 5 days. Safety was assessed and immune parameters measured on day 1 (pre-treatment), 7, 14, and 30 by FACS and by scRNAseq. Results: In vitro, Foralumab preferentially induced CD8+ T cell stimulation, reduced CD4+ T cell proliferation and lowered expression of IFNg, IL-17 and TNFa. Foralumab induced LAP, TIGIT, and KLRG1 immune checkpoint molecules on CD8+ and CD4+ T cells in a mechanism independent of CD8 T cells. In vivo, nasal Foralumab did not modulate CD3 from the T cell surface at any dose. Immune effects were primarily observed at the 50ug dose and consisted of reduction of CD8+ effector memory cells, an increase in naive CD8+ and CD4+ T cells, and reduced CD8+ T cell granzyme B and perforin expression. Differentially expressed genes observed by scRNAseq in CD8+ and CD4+ populations promoted survival and were anti-inflammatory. In the CD8+ TEMRA population there was induction of TIGIT, TGFB1 and KIR3DL2, indicative of a regulatory phenotype. In the memory CD4+ population, there was induction of CTLA4, KLRG1, and TGFB whereas there was an induction of TGF-B1 in naïve CD4+ T cells. In monocytes, there was induction of genes (HLA-DP, HLA-DQ) that promote a less inflammatory immune response. No side effects were observed, and no subjects developed human anti-mouse antibodies. Conclusion: These findings demonstrate that nasal Foralumab is safe and immunologically active in humans and presents a new avenue for the treatment of autoimmune and CNS diseases.

Otolaryngology residents' experiences of pregnancy and return to work: A multisite qualitative study.

Objectives: A paucity of literature exists about childbearing during otolaryngology residency. Pregnancy is a common part of many physician life cycles, but the timing of residency and the rigors of surgical training amplify the challenges. This study was designed to understand the experiences of childbearing otolaryngology residents and support them during this major life event. Unique challenges include long training, shortage of role models, combination surgical and clinical work, and higher rates of infertility. Study Design: Qualitative research. IRB exempt. Setting: United States. Methods: To capture modern perspectives, 16 current and former otolaryngology residents that experienced pregnancy and childbirth during residency in all four geographic regions of the United States in the past 10 years were recruited to participate in individual structured qualitative interviews. Results: Although there was significant training program and personal anxiety reported by childbearing otolaryngology residents, many surgeons experienced healthy pregnancies and postpartum recoveries with minimal disruption to clinical productivity and minimal disruption to their training programs. Multiple recurring themes were identified among the participants spanning the entire childbearing process: increased incidence of pregnancy complications and preterm labor, pregnancy stigma from leadership and coresidents, scheduling logistics regarding call and parental leave, and challenging transitions back to clinical work while navigating breastfeeding and childcare. Conclusion: There are actional recommendations that programs can address to make childbearing during residency accessible and acceptable. Understanding these challenges is an important step to encouraging childbearing residents to prosper in academic otolaryngology, increasing the diversity at the highest levels of the field. Level of Evidence: 4.