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OBJECTIVES/HYPOTHESIS An artificial intelligence (AI) tool was developed using audio clips of cis-male and cis-female voices based on spectral analysis to assess %probability of a voice being perceived as female (%Prob♀). This program was validated with 92% accuracy in cisgender speakers. The aim of the study was to assess the relationship of fo on %Prob♀ by a validated AI tool in a cohort of trans females who underwent intervention to feminize their voice with behavioral modification and/or surgery. STUDY DESIGN Cohort study. METHODS Fundamental frequency (fo ) from prolonged vowel sounds (fo /a/) and fo from spontaneous speech (fo -sp) were measured using the Kay Pentax Computerized Speech Lab (Montvale, NJ) in trans females postintervention. The same voice samples were analyzed by the AI tool for %Prob♀. Chi-square analysis and regression models were performed accepting >50% Prob♀ as female voice. RESULTS Forty-two patients were available for analysis after intervention. fo -sp post-treatment was positively correlated with %Prob♀ (R = 0.645 [P 50% for the speech samples and fo -sp >160 Hz (P 160 Hz. Of these, the AI program only perceived nine patients as female (>50 %Prob♀). CONCLUSION Patients with fo -sp >160 Hz after feminization treatments are not necessarily perceived as having a high probability of being female by a validated AI tool. AI may represent a useful outcome measurement tool for patients undergoing gender affirming voice care. LEVEL OF EVIDENCE 3 Laryngoscope, 131:2567-2571, 2021.

In April 2020, in light of COVID-19-related blood shortages, the US Food and Drug Administration (FDA) reduced the deferral period for men who have sex with men (MSM) from its previous duration of 1 year to 3 months. Although originally born out of necessity, the decades-old restrictions on MSM donors have been mitigated by significant advancements in HIV screening, treatment, and public education. The severity of the ongoing COVID-19 pandemic—and the urgent need for safe blood products to respond to such crises—demands an immediate reconsideration of the 3-month deferral policy for MSM. We review historical HIV testing and transmission evidence, discuss the ethical ramifications of the current deferral period, and examine the issue of noncompliance with donor deferral rules. We also propose an eligibility screening format that involves an individual risk-based screening protocol and, unlike current FDA guidelines, does not effectively exclude donors on the basis of gender identity or sexual orientation. Our policy proposal would allow historically marginalized community members to participate with dignity in the blood donation process without compromising blood donation and transfusion safety outcomes.

Purpose To investigate the influence of abutment material properties on the fracture resistance and failure mode of lithium disilicate (IPS e.max) CAD/CAM (computer-aided design/manufacturing) crowns on traditionally and minimally prepared simulated tooth substrates. Materials and methods Thirty lithium disilicate (IPS e.max) CAD/CAM crowns were divided into three groups (n = 10): TD: traditional thickness crowns cemented on Paradigm MZ100 abutments; MD: minimal thickness crowns cemented on Paradigm MZ100 abutments; ME: minimal thickness crowns cemented on e.max abutments. The 3Shape system was used to scan, design and mill all abutments and crowns with a die space set to 40 µm. Traditional thickness crowns were designed based on manufacturer guidelines with 1.5 mm occlusal thickness and 1.0 mm margins. Minimal thickness crowns were designed with 0.7 mm occlusal thickness and 0.5 mm margins. MZ100 composite and e.max abutments were selected to simulate dentin and enamel substrates, respectively, based on their elastic-modulus. Variolink Esthetic was used to cement all samples following manufacturer's instructions. A universal testing machine was used to load all specimens to fracture with a 3 mm radius stainless steel hemispherical tip at a crosshead speed 0.5 mm/minute along the longitudinal axis of the abutment with a 1 mm thermoplastic film placed between the loading tip and crown surface. Data was analyzed using ANOVA and Bonferroni post hoc assessment. Fractographic analysis was performed with scanning electron microscopy (SEM). Results The mean fracture load (standard deviation) was 1499 (241) N for TD; 1228 (287) N for MD; and 1377 (96) N for ME. Statistically significant difference between groups did not exist (p = 0.157, F = 1.995). In groups TD and MD with low e-modulus abutments, the dispersion of a probability distribution (coefficient of variation: CV) was statistically higher than that of group ME with high e-modulus abutments. SEM illustrated larger micro-fracture dimensions in Group MD than Group ME. Conclusion Minimal thickness e.max crowns did not demonstrate statistical difference in fracture resistance from traditional thickness crowns. Fracture mechanisms of minimal thickness e.max crowns may be affected by the e-modulus of the substrate. Minimal thickness e.max crowns may be a viable restorative option when supported by high e-modulus materials.

Background Treatment options to assist patients to produce a more perceptually feminine voice include voice therapy (VT) and surgeries to elevate pitch such as the Wendler glottoplasty (WG). The Trans Woman Voice Questionnaire (TWVQ) is a validated quality of life measure for trans women's self-reported perceptions of their voice and is frequently administered before and after such interventions. The 30 statements broadly pertain to how feminine a patient feels their voice is, how effortful it is to produce their voice, and how their voice impacts them psychosocially, making it a useful and specific outcome measure when treating trans females for voice concerns. Objective To compare quality of life outcomes between VT and VT with adjunct WG (VT+WG) based on changes in ratings of individual statements on the TWVQ. Materials and Methods A retrospective case series of 31 trans female patients treated was completed. A total of 17 patients underwent VT and 14 underwent VT with adjunctive WG. Ratings for each of the 30 TWVQ statements were compared before and after treatment for each group. Wilcoxon rank-sum tests were used to compare rating changes before and after treatment. Spearman rank-order correlation tests were used to assess the association between total TWVQ score and “current voice” rating. Results WG was associated with statistically significantly improved ratings for every statement on the TWVQ except one. In contrast, VT was associated with statistically significant improvements in 16 of the 30 statements, which largely pertained to patient emotions surrounding their voice rather than physical aspects such as pitch and dysphonia. Furthermore, while both WG+VT and VT improved the “current voice” rating significantly, WG improved the score by nearly 1 unit more. Lastly, we found a positive association between the total TWVQ score and current voice rating, indicating that lower scores were associated with more self-perceived feminine-sounding voices (P Conclusions Both VT and VT+WG result in improvements in the TWVQ. The specific statements on the TWVQ offer insight into specific quality of life treatment outcomes, with VT associated with improvements in mostly psychosocial aspects of voice production and VT+WG with both psychosocial and physical aspects.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living kidney donor biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomics analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for ten years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

OBJECTIVE Burnout is defined as work-related emotional exhaustion, depersonalization, and decreased sense of accomplishment. Virtual reality (VR) has emerged as an effective treatment modality for various conditions related to anxiety, however, few studies have assessed its role for stress management in residents. We hypothesize that VR-based mindfulness meditation can reduce resident burnout in real-world settings. STUDY DESIGN Prospective randomized crossover trial. METHODS Resident participants completed the validated Maslach Burnout Inventory (MBI). One group used a VR-based meditation app; the second group received no intervention. After a 2-month rotation, all subjects completed an MBI and crossed over to the other arm. Wilcoxon rank-sum tests were used to compare MBI scores before and after intervention, and to compare results by gender and postgraduate year. Mann-Whitney U tests were used to assess qualitative differences between participants. RESULTS Eighteen residents completed the study. Five participants were female and 13 were male. Weekly use of VR-guided meditation and paced breathing was associated with a significant decrease in emotional exhaustion (P = .009), and on subgroup analysis, male gender specifically was associated with a decrease in emotional exhaustion (P = .027). In the post-intervention survey, 42.9% subjects reported that VR encouraged them to employ paced breathing techniques, 71.4% reported that they would use the technology if regularly available, and 21.4% reported they would use paced breathing in the future. CONCLUSION VR-based therapy may serve as a successful tool in stress management and reduce the rate of burnout among otolaryngology residents. LEVEL OF EVIDENCE NA Laryngoscope, 131:1972-1976, 2021.

OBJECTIVES The ideal timing and technique of tracheostomy vary among patients and may impact outcomes. We aim to examine the association between tracheostomy timing, placement technique, and patient demographics on survival. STUDY DESIGN Retrospective cohort study. METHODS A retrospective review was performed for all patients who underwent tracheostomy in 2016 and 2017 at one urban academic tertiary-care hospital. Kaplan-Meier curves were created based on combinations of tracheostomy timing and technique (early percutaneous, early non-percutaneous, late percutaneous, and late non-percutaneous). Cox proportional hazard models were used to determine multivariable effects of timing, technique, and other demographic factors. Primary outcome measures were tracheostomy-related mortality and overall survival. Secondary outcomes were in-hospital, 30-day, and 90-day mortality. RESULTS Our study included 523 patients. There were six tracheostomy-related deaths, with hemorrhage and tracheoesophageal fistula being the most common causes. Tracheostomy timing and technique combinations were not associated with differences in all-cause mortality or survival following discharge. Cox proportional hazard models showed that Charlson Comorbidity Index (CCI) and unknown partner status were associated with a decrease in survival (P

OBJECTIVES/HYPOTHESIS Little data exists regarding the relationship between socioeconomic and demographic factors and tracheostomy outcomes. The goal of this study was to determine associations between socioeconomic status (SES), demographic factors, and insurance status with hospital length of stay (LOS), intensive care unit (ICU) LOS, and mortality following tracheostomy. STUDY DESIGN Retrospective cohort study. METHODS A retrospective analysis of all patients who underwent tracheostomy at an urban tertiary-care academic hospital from 2016 to 2017 was performed. Patients were aggregated into low-, middle-, and high-income brackets. Other variables included age, sex, race, ethnicity, body mass index, and Charlson Comorbidity Index (CCI). Outcomes included hospital and ICU LOS, in-hospital mortality, and 30-day mortality following tracheostomy. Outcomes were compared using Kruskal-Wallis tests for continuous variables and χ2 or Fisher exact tests for categorical variables. The α level was set to .05. RESULTS In total, 523 patients were included in the study. Patients from high-income areas were more likely to be male (P

Resiquimod is a synthetic small molecule agonist of Toll-like receptors 7 and 8 (TLR-7/8) that modulates innate immune cells. We found TLR-7/8 are expressed in medulloblastoma exclusively by tumor-associated myeloid cells (TAMs). We tested whether systemically administered resiquimod modulated TAMs in a genetic Sonic hedgehog (SHH) medulloblastoma model, and whether this modulation would be therapeutically beneficial. We generated mice with medulloblastoma by crossing hGFAP-Cre and SmoM2 mouse lines. The resulting hGFAP-Cre/SmoM2 (G-Smo) mice developed medulloblastoma with 100% frequency and showed a median survival of 14.5 days (n=12). Treatment with 3 doses of resiquimod at postnatal days 10, 12 and 14 reduced tumor size and increased median survival to 37 days (n=10) (p=0.003508). Cellular studies showed that resiquimod altered TAM phenotype, rapidly inducing expression of the inflammatory marker VCAM1, and more slowly increasing TAM populations. Responses to the 3-dose regimen were ultimately limited by recurrence and all mice eventually died of tumor progression. Continued resiquimod therapy with every other day dosing was less effective than the 3-dose regimen, suggesting that TAM responses to resiquimod are dynamic and change with prolonged exposure. Our data show that innate immunity, mediated by TAMs and stimulated by TLR-7/8 agonist therapy, can produce a significant anti-tumor effect in medulloblastoma. The common expression of TLR-7/8 on TAMs in patient-derived medulloblastoma samples and in the mouse model suggests that resiquimod may produce similar anti-medulloblastoma effects in humans. Further studies are needed to define the mechanism of the anti-tumor effect in detail, to determine the optimal dose regimen, and to determine if resiquimod can combine effectively with additional adjuvant therapies to produce curative effects.

BACKGROUND New, non-cytotoxic treatments may improve outcomes for medulloblastoma, the most common malignant pediatric brain tumor. Sonic hedgehog (SHH) subgroup medulloblastoma, which includes subtypes with poor prognosis, can be modeled in immunocompetent, transgenic mice. These models are ideal for preclinical testing of immunotherapies. Here, we show that immune stimulation using resiquimod, a small molecule agonist of Toll-like receptor 7 and 8 (TLR 7/8), alters myeloid populations in medulloblastoma and significantly reduces tumor growth. METHOD We generated mice with medulloblastoma by interbreeding the hGFAP-Cre and SmoM2 mouse lines. The resultant hGFAP-Cre/SmoM2 (G-Smo) mice develop SHH medulloblastoma with 100% frequency. We analyzed myeloid populations and demonstrated TLR7/8 expression patterns in G-Smo tumors. We then compared survival of untreated G-Smo mice versus G-Smo mice treated with three doses of resiquimod at postnatal days 10, 12, and 14. We also assessed pharmacodynamic effects at progressive intervals after a single dose. RESULTS Approximately 10% of cells in G-Smo medulloblastomas were myeloid cells, and these cells were the only cells that expressed TLR7/8. Resiquimod slowed tumor growth and increased the survival of mice with medulloblastoma. Untreated median survival was 14.5 days (n=12), compared to resiquimod-treated median survival of 37 days (n=10; p=0.0003). All treated mice eventually demonstrated tumor progression. Immunohistochemistry for IBA1, a pan-macrophage marker, demonstrated significant increase in myeloid cells within the tumor by 24 hours after treatment (p=0.0178), however the IGF1+ fraction of myeloid cells decreased (p=0.0275). CONCLUSION Resiquimod prolongs survival in mice with SHH-driven medulloblastoma, demonstrating the potential for therapies that target myeloid cells to produce significant anti-tumor effects. Myeloid-derived IGF-1 has been shown to support tumor progression and resiquimod may act by disrupting this paracrine signaling.

The purpose of this study is to define value in bundled total joint arthroplasty (TJA) from the differing perspectives of the patient, payer/employer, and hospital/provider.Demographic, psychosocial, clinical, financial, and patient-reported outcomes (PROs) data from 2017 to 2018 elective TJA cases at a multihospital academic health system were queried. Value was defined as improvement in PROs (preoperatively to 1 year postoperatively) for patients, improvement in PROs per $1000 of bundle cost for payers, and the normalized sum of improvement in PROs and hospital bundle margin for providers. Bivariate analysis was used to compare high value vs low value (50th percentile vs50th percentile). Multivariate analysis was performed to identify predictors.A total of 280 patients had PRO data, of which 71 had Medicare claims data. Diabetes (odds ratio [OR], 0.45; P = .02) predicted low value for patients; female gender (OR, 0.25), hypertension (OR, 0.17), pulmonary disease (OR, 0.12), and skilled nursing facility discharge (OR, 0.17) for payers (P ≤ .03 for all); and pulmonary disease (OR, 0.16) and skilled nursing facility discharge (OR, 0.19) for providers (P ≤ .04 for all).This is the first article to define value in TJA under a bundle payment model from multiple perspectives, providing a foundation for future studies analyzing value-based TJA.

Background Heart failure (HF) is a condition that affects approximately 6.2 million people in the United States and has a 5-year mortality rate of approximately 42%. With the prevalence expected to exceed 8 million cases by 2030, projections estimate that total annual HF costs will increase to nearly US $70 billion. Recently, the advent of remote monitoring technology has significantly broadened the scope of the physician’s reach in chronic disease management. Objective The goal of our program, named the Heart Health Program, was to examine the feasibility of using digital health monitoring in real-world home settings, ascertain patient adoption, and evaluate impact on 30-day readmission rate. Methods A digital medicine software platform developed at Mount Sinai Health System, called RxUniverse, was used to prescribe a digital care pathway including the HealthPROMISE digital therapeutic and iHealth mobile apps to patients’ personal smartphones. Vital sign data, including blood pressure (BP) and weight, were collected through an ambulatory remote monitoring system that comprised a mobile app and complementary consumer-grade Bluetooth-connected smart devices (BP cuff and digital scale) that send data to the provider care teams. Care teams were alerted via a Web-based dashboard of abnormal patient BP and weight change readings, and further action was taken at the clinicians’ discretion. We used statistical analyses to determine risk factors associated with 30-day all-cause readmission. Results Overall, the Heart Health Program included 58 patients admitted to the Mount Sinai Hospital for HF. The 30-day hospital readmission rate was 10% (6/58), compared with the national readmission rates of approximately 25% and the Mount Sinai Hospital’s average of approximately 23%. Single marital status (P=.06) and history of percutaneous coronary intervention (P=.08) were associated with readmission. Readmitted patients were also less likely to have been previously prescribed angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (P=.02). Notably, readmitted patients utilized the BP and weight monitors less than nonreadmitted patients, and patients aged younger than 70 years used the monitors more frequently on average than those aged over 70 years, though these trends did not reach statistical significance. The percentage of the 58 patients using the monitors at least once dropped from 83% (42/58) in the first week after discharge to 46% (23/58) in the fourth week. Conclusions Given the increasing burden of HF, there is a need for an effective and sustainable remote monitoring system for HF patients following hospital discharge. We identified clinical and social factors as well as remote monitoring usage trends that identify targetable patient populations that could benefit most from integration of daily remote monitoring. In addition, we demonstrated that interventions driven by real-time vital sign data may greatly aid in reducing hospital readmissions and costs while improving patient outcomes.

Summary Objectives Radiation treatment for laryngeal cancer has been shown to cause tissue changes to the vocal folds, which can result in degradation of voice. Our objective in this study was to investigate changes in perceptual, acoustic, and patient-reported outcomes over an extended period of follow-up after radiation. Design Retrospective review. Methods All patients treated with radiation for early-stage laryngeal carcinoma (in situ, T1, or T2) by a single surgeon from 2011–2018 were reviewed. Demographics and treatment information were recorded. Only patients with at least two dates of follow-up with acoustic data (cepstral spectral index of dysphonia [CSID]) and patient-reported surveys (voice handicap index-10 [VHI-10]) were included. Voice samples were rated by two senior speech-language pathologists on the grade, roughness, breathiness, asthenia, and strain scale. Results Of 115 patients with early-stage laryngeal cancer, 31 patients met inclusion criteria. The average follow-up from time of treatment was 9.6 years (range 3.0–20.3 years), and the average time in between the first and last voice recordings was 2.6 years (range 0.3–5.5 years). The lesions represented were carcinoma in situ (n = 4), T1 (n = 22), and T2 (n = 5). The VHI-10 scores worsened slightly (mean increase +0.27, median +1) from first to last measurements as did the CSID score (median increase +7.0, median +7.4), though neither reached statistical significance when correlated with time since radiation (P = 0.269 and P = 0.0850). Perceptual analysis as rated by two speech-language pathologists raters showed excellent inter-rater reliability (Cronbach's alpha = 0.84), with no significant change over time (mean +0.39, median, with P = 0.347). Grade, roughness, breathiness, asthenia, and strain, VHI-10, and CSID were all correlated (all pairwise comparisons P Conclusion Perceptual, acoustic, and patient-reported outcomes years after radiation for early-stage laryngeal cancer do not show voice degradation over time in this preliminary analysis. Further research with a larger cohort may elucidate voice changes in this population.

Background: Multiple myeloma (MM) is a clonally heterogeneous cancer that recurrently relapses during its clinical course, demonstrating how interplay among subclones can lead to differentially drug-tolerant populations. The determination of onset and mechanisms of drug resistance is of clinical interest, and the improved understanding of this will drive innovative therapeutic approaches. The IMiD® agents lenalidomide (Len) and pomalidomide (Pom) bind to the E3-ubiquitin ligase receptor, Cereblon (CRBN), leading to ubiquitination and subsequent proteosomal degradation of key transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). As a consequence of this degradation, direct antitumor and immunostimulatory effects are observed. Previous studies have revealed potential mechanisms of resistance to Len and Pom in both MM cell lines and clinical cohorts, including mutations, transcriptional downregulation or alternative splicing of CRBN, or mutations elsewhere in the E3 ligase pathway (CUL4A, DDB1), IKZF1/3 or IRF4. In resistant cell lines and patients, activation of proliferation, cell cycle, IGF-1, MAPK and FOXM1 pathways are reported, in addition to non-activation of interferon signature genes (ISGs). We hypothesize that rare MM cells/subclones with genetic, epigenetic or proteomic architecture permitting survival against Len or Pom in vitro may exist prior to acquired resistance, but may not be detectable by bulk genomic, transcriptional or proteomic analyses. Our goal is to define such populations using a combination of single cell technologies, initially focusing on acquired Pom-resistance mechanisms and quantifying genetic and transcriptional changes in Cereblon and its mechanistic targets, and to identify features of pre-existing resistant cell populations. Methods: To investigate the mechanism and timing of onset of acquired resistance, we utilized H929 and MM1S MM cell lines made resistant to Pom by serial dose increments over time, to a final Pom concentration of 10 μM (H929/PR and MM1S/PR respectively). Samples were collected at various timepoints for analysis by genomic, bulk and single cell (10X genomics) RNASeq techniques, and single cell protein quantification of Cereblon, Ikaros and Aiolos by IHC. Results: Bulk genomic sequencing revealed the H929/PR cell line had gained two CRBN mutations, a frameshift deletion of the glutarimide-binding region present in 10.9% alleles, and a point mutation in the non-glutarimide binding region present in 71% alleles. Concurrent single-cell protein quantification showed a near complete loss of Cereblon expression in the majority of cells, with little change in Ikaros or Aiolos staining. Bulk RNASeq of the H929/PR cell line showed a significant enrichment of cell cycle, E2F and MYC target gene sets. Using single cell transcriptomics, we found high expression of the signature genes of the Pom-resistant population to co-localise with an independently derived FOXM1 target gene set to a cluster of sensitive single cells defined by a gene expression profile identifying cells at the G2M checkpoint. Sanger sequencing of CRBN in the MM1S/PR cell line showed a de novo 12 bp deletion in intron 5 which is required for spliceosome assembly, resulting in deletion of exon 6 of the mature mRNA transcript. Interestingly, CRBN exon 6 is required for interaction with DDB1, suggesting loss of a functional E3-ligase. Analysis by single cell IHC showed substrate levels similar to sensitive parental cell lines. As in the H929/PR cell line, bulk RNASeq again showed enrichment of E2F and MYC targets, and independently derived Pom-resistant and FOXM1 target gene sets co-localised to the same cluster of MM1S drug-naïve single cells, identified by a G2M checkpoint signature. Conclusions: A range of CRBN mutations, Cereblon protein loss and enrichment of cell cycle, FOXM1 target and G2M checkpoint-related signatures was found at the onset of Pom resistance. This association with altered cell cycle progression dynamics may lead to, correlate with or result from drug survival. Tracking mutation- and non mutation-associated transcription factor signatures through sequential time points from first drug exposure to full resistance may reveal mechanisms by which functional CRBN loss causes drug resistance. Disclosures Gooding: Celgene: Research Funding. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Ren:Celgene Corporation: Employment, Equity Ownership. Marella:Celgene: Employment. Couto:Celgene: Employment. Towfic:Celgene Corporation: Employment, Equity Ownership. Oppermann:Bayer Pharma: Research Funding. Ramasamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pierceall:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership.