The presence of fear: How subjective fear, not physiological changes, shapes the experience of presence.

When we become engrossed in novels, films, games, or even our own wandering thoughts, we can feel present in a reality distinct from the real world. Although this subjective sense of presence is, presumably, a ubiquitous aspect of conscious experience, the mechanisms that produce it are unknown. Correlational studies conducted in virtual reality have shown that we feel more present when we are afraid, motivating claims that physiological changes contribute to presence; however, such causal claims remain to be evaluated. Here, we report two experiments that test the causal role of subjective and physiological components of fear (i.e., activation of the sympathetic nervous system) in generating presence. In Study 1, we validated a virtual reality simulation capable of inducing fear. Participants rated their emotions while they crossed a wooden plank that appeared to be suspended above a city street; at the same time, we recorded heart rate and skin conductance levels. Height exposure increased ratings of fear, presence, and both measures of sympathetic activation. Although presence and fear ratings were correlated during height exposure, presence and sympathetic activation were unrelated. In Study 2, we manipulated whether the plank appeared at height or at ground level. We also captured participants' movements, which revealed that alongside increases in subjective fear, presence, and sympathetic activation, participants also moved more slowly at height relative to controls. Using a mediational approach, we found that the relationship between height exposure and presence on the plank was fully mediated by self-reported fear, and not by sympathetic activation. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment.

The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor-infiltrating T cells (TILs), hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. We reveal that the solid TME imposes perpetual acetyl-coenzyme A (CoA) carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, which sustains cancer control.

Melatonin protects against cadmium-induced oxidative stress via mitochondrial STAT3 signaling in human prostate stromal cells.

Melatonin protects against Cadmium (Cd)-induced toxicity, a ubiquitous environmental toxicant that causes adverse health effects by increasing reactive oxygen species (ROS) production and mitochondrial dysfunction. However, the underlying mechanism remains unclear. Here, we demonstrate that Cd exposure reduces the levels of mitochondrially-localized signal transducer and activator of transcription 3 (mitoSTAT3) using human prostate stromal cells and mouse embryonic fibroblasts. Melatonin enhances mitoSTAT3 abundance following Cd exposure, which is required to attenuate ROS damage, mitochondrial dysfunction, and cell death caused by Cd exposure. Moreover, melatonin increases mitochondrial levels of GRIM-19, an electron transport chain component that mediates STAT3 import into mitochondria, which are downregulated by Cd. In vivo, melatonin reverses the reduced size of mouse prostate tissue and levels of mitoSTAT3 and GRIM-19 induced by Cd exposure. Together, these data suggest that melatonin regulates mitoSTAT3 function to prevent Cd-induced cytotoxicity and could preserve mitochondrial function during Cd-induced stress.

Game of clones: Diverse implications for clonal hematopoiesis in lymphoma and multiple myeloma.

Clonal hematopoiesis (CH) refers to the disproportionate expansion of hematopoietic stem cell clones and their corresponding progeny following the acquisition of somatic mutations. CH is common at the time of diagnosis in patients with blood cancers, including multiple myeloma (MM) and lymphoma. The presence of CH mutations correlates with IL-6 mediated inflammation and may result in lymphoma or MM modulation through microenvironment effects or by manifestations of the mutations themselves within the founding tumor clone. As might be expected with a variety of mutations and multiple potential mechanisms, CH exerts context-dependent effects, being protective in some settings and harmful in others. Though CH is very common in patients with hematologic malignancies, how it intersects with therapy and the natural disease course of these cancers are active areas of investigation. In lymphomas and MM specifically, patients have high rates of CH at diagnosis and are subsequently exposed to therapies, such as cytotoxic chemotherapy, that can cause CH progression to overt hematologic malignancy. The expanding diversity of treatment modalities for these cancers also increases the opportunities for CH to impact clinical outcome and modulate clinical responses. Here we review the basic biology and known health effects of CH, and we focus on the clinical relevance of CH in lymphoma and MM.

The Emerging Role of CAR T Cell Therapy in Relapsed/Refractory Hodgkin Lymphoma.

Treatment for Hodgkin lymphoma (HL) has evolved considerably from the time it was originally described in the 19th century with many patients now being cured with frontline therapy. Despite these advances, upwards of 10% of patients experience progressive disease after initial therapy with an even higher percentage relapsing. Until recently there had been limited therapeutic options for relapsed and/or refractory HL outside of highly intensive chemotherapy with stem cell rescue. Improved understanding of the pathophysiology of HL, coupled with the emergence of more targeted therapeutics, has reshaped how we view the treatment of relapsed/refractory HL and its prognosis. With this, there has been an increased focus on immunotherapies that can reprogram the immune system to better overcome the immunosuppressive milieu found in HL for improved cancer cell killing. In particular, chimeric antigen receptor (CAR) T cells are emerging as a valuable therapeutic tool in this area. Building on the success of antibody-drug conjugates directed against CD30, CAR T cells engineered to recognize the same antigen are now reaching patients. Though still in its infancy, CAR T therapy for relapsed/refractory HL has shown exceptional promise in early-stage clinical trials with the potential for durable responses even in patients who had progressed through multiple lines of prior therapy. Here we will review currently available data on the use of CAR T cells in HL, strategies to optimize their effectiveness, and how this therapy may fit into the treatment paradigm of HL going forward.

B Cell Function in the Tumor Microenvironment.

The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.

A subset of follicular helper-like MAIT cells can provide B cell help and support antibody production in the mucosa.

Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that aid in protection against bacterial pathogens at mucosal surfaces through the release of inflammatory cytokines and cytotoxic molecules. Recent evidence suggests that MAIT cells can also provide B cell help. In this study, we describe a population of CXCR5+ T follicular helper (Tfh)­like MAIT cells (MAITfh) that have the capacity to provide B cell help within mucosal lymphoid organs. MAITfh cells are preferentially located near germinal centers in human tonsils and express the classical Tfh-associated transcription factor, B cell lymphoma 6 (BCL-6), the costimulatory markers inducible T cell costimulatory (ICOS) and programmed death receptor 1 (PD-1), and interleukin-21 (IL-21). We demonstrate the ability of MAIT cells to provide B cell help in vivo after mucosal challenge with Vibrio cholerae. Specifically, we show that adoptive transfer of MAIT cells into αß T cell­deficient mice promoted B cell differentiation and increased serum V. cholerae­specific IgA responses. Our data demonstrate the capacity of MAIT cells to participate in adaptive immune responses and suggest that MAIT cells may be potential targets for mucosal vaccines.

Deductible Status in the Pediatric Population: A Barrier to Appropriate Care?

OBJECTIVE: The objective of this study is to evaluate the impact of high-deductible health plans on elective surgery (tonsillectomy) in the pediatric population. STUDY DESIGN: Cross-sectional study. SETTING: Health claims database from a third-party payer. METHODS: Data were reviewed for children up to 18 years of age who underwent tonsillectomy or arm fracture repair (nonelective control) from 2016 to 2019. Incidence of surgery by health plan deductible (high, low, or government insured) and met or unmet status of deductibles were compared. RESULTS: A total of 10,047 tonsillectomy claims and 9903 arm fracture repair claims met inclusion and exclusion criteria. The incidence of tonsillectomy was significantly different across deductible plan types. Patients with met deductibles were more likely to undergo tonsillectomy. In patients with deductibles ≥$4000, a 1.75-fold increase in tonsillectomy was observed in those who had met their deductible as compared with those who had not. These findings were not observed in controls (nonelective arm fracture). For those with met deductibles, those with high deductibles were much more likely to undergo tonsillectomy than those with low, moderate, and government deductibles. Unmet high deductibles were least likely to undergo tonsillectomy. CONCLUSIONS: Health insurance plan type influences the incidence of pediatric elective surgery such as tonsillectomy but not procedures such as nonelective repair of arm fracture. High deductibles may discourage elective surgery for those deductibles that are unmet, risking inappropriate care of vulnerable pediatric patients. However, meeting the deductible may increase incidence, raising the question of overutilization.

Personality in Children With Vocal Fold Nodules: A Multitrait Analysis.

Purpose Vocal fold nodules (VNs) are bilateral, symmetrical, callous-like lesions secondary to phonotrauma and possibly related to specific personality traits. This case-control study examined the relation between personality and VNs in children within the context of the Trait Theory of VNs. Method Parents of children with VNs (N = 39, M = 7.43, SD = 2.01 years) and two medical control groups (i.e., voice disordered controls, but not VNs [VDCs; N = 40, M = 7.09, SD = 2.01 years] and vocally normal controls [VNCs; N = 40, M = 7.6, SD = 1.54 years]) completed the Inventory of Child Individual Differences, a personality instrument that describes the Big Five superfactors as well as 15 lower order personality traits. Results Children with VNs, as compared with VNCs, were (a) emotionally reactive (i.e., higher N-Neuroticism, p < .005, Cohen's d = 0.53), (b) Antagonistic, Strong-Willed, and less Compliant (i.e., lower A-Agreeableness, p < .014, Cohen's d = 0.59), and (c) Distractible and Disorganized (i.e., lower C-Conscientiousness, p < .009, Cohen's d = 0.62). Both voice disordered groups displayed elevated scores on the personality superfactor of Neuroticism (N; and the "Negative Emotions" lower order trait). Conclusions The combination of personality traits identified in this study (i.e., high N, low A and C) may play a central role in VNs development and possibly attenuate voice therapy success. Children with VNs displayed a similar personality typology as women with VNs, with the exception of elevated Extraversion (E), thereby providing support for the relevance of the Trait Theory of VNs in both children and adults. Clinicians treating children with voice disorders, including VNs, should consider their underlying personality traits in assessment and management.

Slide Tracheoplasty for Tracheal Cartilaginous Sleeve in a Patient With Apert Syndrome.

Apert syndrome is a form of acrocephalosyndactyly involving craniosynostosis, syndactyly, and less commonly, tracheal cartilaginous sleeve (TCS), a potential cause of tracheal stenosis. Slide tracheoplasty is performed in children with tracheal stenosis. No reports exist for its application in stenosis related to TCS. We present a case in which slide tracheoplasty was used for the expansion of long segment tracheal stenosis owing to TCS in a newborn with Apert syndrome. Using this technique, a safe and durable airway was achieved without tracheostomy.

Are Opioids Necessary in Middle Ear Surgery? Comparing the Transcanal and Postauricular Approach.

OBJECTIVE: Understand opioid-prescribing patterns in otologic surgery and the difference in opioid use between transcanal and postauricular surgery. STUDY DESIGN: Prospective survey. SETTING: Multihospital network. PATIENTS: All patients undergoing otologic surgery from March 2017 to January 2019. INTERVENTION: Patients undergoing otologic surgery were surveyed regarding postoperative opioid use and their level of pain control. Patients were divided by surgical approach (transcanal vs. postauricular). Those who underwent mastoid drilling were excluded. Narcotic amounts were converted to milligram morphine equivalents (MME) for analysis. MAIN OUTCOME MEASURES: Amount of opioid was calculated and compared between the two groups. Mann-Whitney U test and Chi-square testing were used for analysis. RESULTS: Fifty-five patients were included in the analysis; of these 18 (33%) had a postauricular incision. There was no difference in age (p = 0.85) or gender (p = 0.5) between the two groups. The mean amount of opioid prescribed (MME) in the postauricular and transcanal groups was 206.4 and 143 (p = 0.038) while the mean amount used was 37.7 and 37.5 (p = 0.29) respectively. There was no difference in percentage of opioid used (p = 0.44) or in patient-reported level of pain control (p = 0.49) between the two groups. CONCLUSION: Patients in both the transcanal and postauricular groups used only a small portion of their prescribed opioid. There was no difference in the amount of opioid used or the patient's reported level of pain control based on the approach. Otologic surgeons should be aware of these factors to reduce narcotic diversion after ear surgery.

Survival Differences Between Pediatric Head and Neck Versus Body Melanoma in the Surveillance, Epidemiology, and End Results Program.

OBJECTIVES/HYPOTHESIS: To review the demographics, treatment, and survival of pediatric melanoma of the head and neck and to determine if melanoma of the head and neck has worse survival than melanoma of other body sites. STUDY DESIGN: Retrospective database review. METHODS: Pediatric patients from 0 to 21 years in the Surveillance, Epidemiology, and End Results 18 registries database were included from 1975 to 2016 based on a diagnosis of melanoma of the skin using the primary site International Classification of Diseases for Oncology, Third Edition codes from C44.0-C44.9.skin of lip, C44.1-eyelid, C44.2-external ear, C44.3-skin other/unspecified parts of face, C44.4-skin of scalp and neck, C44.5-skin of trunk, C44.6-skin of upper limb and shoulder, C44.7-skin of lower limb and hip, C44.8-overlapping lesion of skin, and C44.9-skin, NOS (not otherwise specified). RESULTS: A total of 4,561 pediatric melanomas of the skin were identified. There were 854 (18.7%) cases of melanoma of the head and neck (MHN) and 3,707 (81.3%) cases of melanoma of the body (MOB). The hazard ratio for MHN versus MOB was 1.6 (95% confidence interval: 1.3-2.1) after accounting for sex, race, and age. Of MHN sites, the hazard ratio for melanoma of the scalp and neck was 2.2 (1.1-4.7). The 2- and 5-year Kaplan-Meier overall survival for MHN were 94.6% and 90.7%, respectively, compared with 96.6% and 94.7%, respectively, for MOB (P < .01). CONCLUSIONS: Survival outcomes of pediatric melanoma are notably related to anatomic site. Children with melanoma of the scalp and neck have the worst survival of all sites. Additionally, children who are older/white/male are at greater risk for worse survival outcomes. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E635-E641, 2021.

Evaluation of opioid prescription patterns among patients undergoing thyroid surgery.

BACKGROUND: There is variability in opioid prescription patterns among surgeons performing thyroidectomy. Thus, the aim of this study is to evaluate opioid prescription rates and opioid use among hemithyroidectomy (HT) and total thyroidectomy (TT) patients. DESIGN/METHOD: An electronic postoperative survey was distributed to assess opiate use among patients undergoing HT/TT. Groups were compared using t-tests, chi-square tests, and analysis of variance. RESULTS: A total of 142 opiate naïve patients were included, of which 75 (52.8%) underwent HT and 67 (47.1%) underwent TT. The mean number of tablets prescribed was 21.3 (HT = 22.1, TT = 20.4; P = 0.3), with a mean of 14.1 tablets unused after surgery (HT = 13.2 tablets, TT = 15.0 tablets; P = 0.44). The mean morphine milligram equivalent (MME) prescribed was 150.1 mg (HT = 159.0 mg, TT = 140.2 mg; P = 0.3), with a mean of 98.2 MME unused after surgery (HT = 93.7 mg, TT = 103.2 mg; P = 0.6). CONCLUSIONS: Opioids are overprescribed after thyroid surgery. Avoidance of overprescribing is vital in mitigating the current opioid crisis.

Management of Velopharyngeal Insufficiency in Cleft Patients With and Without Multidisciplinary Team Care.

OBJECTIVE: To evaluate the effect of an American Cleft Palate-Craniofacial Association (ACPA)-approved multidisciplinary team on velopharyngeal insufficiency (VPI) diagnosis and treatment. DESIGN: Retrospective cohort setting; tertiary children's hospital patients; children with cleft palate repair identified through procedure codes. MAIN OUTCOME MEASURES: Velopharyngeal insufficiency diagnosis was assigned based on surgeon or team assessment. Age at diagnosis and surgery was recorded. Difference in age and rate of VPI diagnosis and surgery was analyzed with t test. Multivariate linear and logistic regression adjusted for confounding variables. RESULTS: Nine hundred forty patients were included with 71.5% cared for by an ACPA-approved multidisciplinary team. More (38.8% ) team care patients were found to have a diagnosis of VPI in comparison to 10% in independent care (P < .001). Team care was associated with an almost 6-fold increase in VPI diagnosis (P < .001). Team care was associated with a higher proportion of speech surgery (21% vs 10%, P < .001). Among children receiving team care, each visit was associated with 25% increased odds of being diagnosed with VPI (P < .001) and 20% increased odds of receiving speech surgery (P < .001). Age at VPI diagnosis and speech surgery were similar between groups (P = .55 and .29). DISCUSSION: Team care was associated with more accurate detection of VPI, resulting in more VPI speech therapy visits and surgical management. A higher number of team visits were similarly associated. CONCLUSION: Further studies of the clinical implication of timely and accurate VPI diagnosis, including quality of life assessments, are recommended to provide stronger guidance on team visit and evaluation planning.

What Is the Impact of Prior Authorization on the Incidence of Pediatric Tonsillectomy?

OBJECTIVE: Third-party payers advocate for prior authorization (PA) to reduce overutilization of health care resources. The impact of PA in elective surgery is understudied, especially in cases where evidence-based clinical practice guidelines define operative candidacy. The objective of this study is to investigate the impact of PA on the incidence of pediatric tonsillectomy. STUDY DESIGN: Cross-sectional study. SETTING: Health claims database from a third-party payer. METHODS: Any pediatric patient who had evaluation for tonsillectomy from 2016 to 2019 was eligible for inclusion. A time series analysis was used to evaluate the change in incidence of tonsillectomy before and after PA. Lag time from consultation to surgery before and after PA was compared with segmented regression. RESULTS: A total of 10,047 tonsillectomy claims met inclusion and exclusion criteria. Female patients made up 51% of claims, and the mean age was 7.9 years. Just 1.5% of claims were denied after PA implementation. There was no change in the incidence of tonsillectomy for all plan types (P = .1). Increased lag time from consultation to surgery was noted immediately after PA implementation by 2.38 days (95% CI, 0.23-4.54; P = .030); otherwise, there was no significant change over time (P = .98). CONCLUSION: A modest number of tonsillectomy claims were denied approval after implementation of PA. The value of PA for pediatric tonsillectomy is questionable, as it did not result in decreased incidence of tonsillectomy in this cohort.

Radiofrequency Ablation vs Electrocautery Blinded Randomized Trial: Impact on Clinically Meaningful Outcomes.

OBJECTIVE: To analyze patients' return to normal activity, pain scores, narcotic use, and adverse events after undergoing tonsillectomy or adenotonsillectomy with monopolar electrocautery or radiofrequency ablation. STUDY DESIGN: Randomized double-blinded clinical trial based on prospective parallel design. SETTING: Academic medical center and tertiary children's hospital between March 2018 and July 2019. METHODS: Inclusion criteria included patients aged ≥3 years with surgical indication of recurrent tonsillitis or airway obstruction/sleep-disordered breathing. Patients were randomly assigned to monopolar electrocautery or radiofrequency ablation. Patients were blinded to treatment assignment. Survey questions answered via text or email were collected daily until postoperative day 15. The primary outcome was the patient's return to normal activity. Secondary outcomes included daily pain score, total amount of postoperative narcotic use, and adverse events. RESULTS: Of the 236 patients who met inclusion criteria and were randomly assigned to radiofrequency ablation or monopolar electrocautery, 230 completed the study (radiofrequency ablation, n = 112; monopolar electrocautery, n = 118). There was no statistically significant difference between the groups in the number of days for return to normal activity (P = .89), daily pain scores over 15 postoperative days (P = .46), postoperative narcotic use (P = .61), or return to hospital for any reason (P = .60), including bleeding as an adverse event (P = .13). CONCLUSIONS: As one of the largest randomized controlled trials examining instrumentation in tonsillectomy, our data do not show a difference between monopolar electrocautery and radiofrequency ablation with regard to return to normal activity, daily pain scores, total postoperative narcotic use, or adverse events.

Inter-rater reliability in diagnosis and treatment of type one laryngeal cleft: A blinded observational study.

INTRODUCTION: Type one laryngeal cleft (T1LC) has been implicated as a major contributor to aspiration in non-syndromic pediatric dysphagia. Despite an increasing incidence, there remains controversy in diagnosis and treatment algorithms. OBJECTIVES: The primary objective of this study was to evaluate the inter-rater reliability (IRR) for the diagnosis and treatment of T1LC. METHODS: A retrospective analysis was conducted to identify children evaluated for a T1LC from 2016 to 2017 at a single tertiary care center. The microlaryngoscopy video recordings depicting palpation of the interarytenoid region with a right-angle probe were reviewed. These recordings were shown to blinded pediatric otolaryngologists and each surgeon's determination of the presence or absence of a T1LC as well as recommended treatment (observation, injection laryngoplasty, or endoscopic cleft repair) was recorded and compared against the other blinded surgeons. Fleiss's kappa was calculated to evaluate IRR in both diagnosis and treatment. RESULTS: Eight pediatric otolaryngologists were included in the study with a mean post-training experience of 15 years (range 1-35 years). The inter-rater percent agreement in diagnosis of our patient population was 28.6% (range 3.7-71%) with a kappa value of 0.31 (p < 0.0001). In regard to management, the inter-rater percent agreement in treatment was 11.4% (range 0-35%) with a kappa value of 0.14 (p = 0.01). CONCLUSION: This study highlights the challenges and variation that exists among surgeons in diagnosing and managing potential T1LC. Further standardizing the endoscopic examination and treatment algorithm may reduce diagnostic and treatment discordance.