CRISPR-dCas13d-based deep screening of proximal and distal splicing-regulatory elements.

Pre-mRNA splicing, a key process in gene expression, can be therapeutically modulated using various drug modalities, including antisense oligonucleotides (ASOs). However, determining promising targets is hampered by the challenge of systematically mapping splicing-regulatory elements (SREs) in their native sequence context. Here, we use the catalytically inactive CRISPR-RfxCas13d RNA-targeting system (dCas13d/gRNA) as a programmable platform to bind SREs and modulate splicing by competing against endogenous splicing factors. SpliceRUSH, a high-throughput screening method, was developed to map SREs in any gene of interest using a lentivirus gRNA library that tiles the genetic region, including distal intronic sequences. When applied to SMN2, a therapeutic target for spinal muscular atrophy, SpliceRUSH robustly identifies not only known SREs but also a previously unknown distal intronic SRE, which can be targeted to alter exon 7 splicing using either dCas13d/gRNA or ASOs. This technology enables a deeper understanding of splicing regulation with applications for RNA-based drug discovery.

Is a Simple Checklist Associated With Improvement in Gender Representation at the AAO-HNSF Annual Meeting?

OBJECTIVE: In September 2017, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) added 2 questions querying panel organizers if gender/racial diversity was considered in selecting panel presenters, beginning with the 2018 Annual Meeting (AM). This study examines how this checklist impacted the gender diversity of panel presenters at the AAO-HNS AM. STUDY DESIGN: This was a cross-sectional investigation comparing female representation before and after the addition of questions inquiring about diversity in 2018. SETTING: A review of abstract submissions for the AMs from 2015 to 2021. METHODS: AM Official Program Abstracts were used to obtain presenter names and specialty area for each panel. The percentage of female presenters, in total and stratified by specialty area, were compared before and after 2018 to quantify changes following the addition of the checklist. RESULTS: There was a significant increase in the proportion of female panel presenters from 22.3% (total n = 1199) in 2015 to 2017 to 33.0% (total n = 1868) in 2018 to 2021 (P < .001) and in all panel specialties. The number of female moderated panels also significantly increased after checklist implementation from 22% to 38% (P < .001). Correspondingly, the number of panels with no female representation decreased from 42% in 2015 to 2017 to 23% in 2018 to 2021 (P < .001). CONCLUSION: The addition of a checklist asking panel organizers to consider diversity in selecting panelists was associated with an increased proportion of female presenters at the AM. This simple strategy can be implemented by all medical conferences to help close the gender gap.

Deep screening of proximal and distal splicing-regulatory elements in a native sequence context.

Pre-mRNA splicing, a key process in gene expression, can be therapeutically modulated using various drug modalities, including antisense oligonucleotides (ASOs). However, determining promising targets is impeded by the challenge of systematically mapping splicing-regulatory elements (SREs) in their native sequence context. Here, we use the catalytically dead CRISPR-RfxCas13d RNA-targeting system (dCas13d/gRNA) as a programmable platform to bind SREs and modulate splicing by competing against endogenous splicing factors. SpliceRUSH, a high-throughput screening method, was developed to map SREs in any gene of interest using a lentivirus gRNA library that tiles the genetic region, including distal intronic sequences. When applied to SMN2, a therapeutic target for spinal muscular atrophy, SpliceRUSH robustly identified not only known SREs, but also a novel distal intronic splicing enhancer, which can be targeted to alter exon 7 splicing using either dCas13d/gRNA or ASOs. This technology enables a deeper understanding of splicing regulation with applications for RNA-based drug discovery.

Do Racial and Ethnic Disparities Exist in Management of Pediatric Mandible Fractures? A 30-Year Outcome Analysis.

BACKGROUND: Mandibular fractures are the most common of pediatric facial fractures. The effect of race on management/outcomes in these injuries has not been previously studied. Given the significant association between race and healthcare outcomes in many other pediatric conditions, an in-depth study of race as related to mandibular fractures in the pediatric patient population is warranted. METHODS: This was a 30-year retrospective, longitudinal study of pediatric patients who presented to a single institution with mandibular fractures. Patient data were compared between patients of different races and ethnicities. Demographic variables, injury characteristics, and treatment variables were analyzed to find predictors of surgical treatment and posttreatment complications. RESULTS: One hundred ninety-six patients met inclusion criteria, of whom 49.5% were White, 43.9% were Black, 0.0% were Asian, and 6.6% were classified as "other." Black and "other" patients were more likely than their White counterparts to be injured as pedestrians (P = 0.0005). Black patients were also more likely than White patients or "other" patients to be injured by assault than by sports-related injuries or animal-related accidents (P = 0.0004 and P = 0.0018, respectively). Race or ethnicity were not found to be a predictor of receiving surgical treatment (ORIF) or of posttreatment complications. The posttreatment rates for all the complications observed were comparable among all race and ethnic groups. Higher mandible injury severity score (odds ratio [OR], 1.25), condyle fracture (OR, 2.58), and symphysis fracture (OR, 3.20) were positively correlated with receiving ORIF as treatment. Mandible body fracture (OR, 0.36), parasymphyseal fracture (OR, 0.34), bilateral mandible fracture (OR, 0.48), and multiple mandibular fractures (OR, 0.34) were negatively correlated with receiving ORIF as treatment. Only high mandible injury severity score (OR, 1.10) was identified as an independent predictor of posttreatment complications. Lastly, Maryland's transition to an all-payer model in 2014 also had no impact on treatment modality; treatment of fractures among race and ethnicity were not significantly different pre- and post-2014. CONCLUSIONS: There is no difference in how patients are treated (surgically vs nonsurgically) and no difference in outcomes for patients based on race at our institution. This could be due to institutional ideology, services provided by a tertiary care center, or simply the more diverse patient population at baseline.

Olfactory Dysfunction and Balance Dysfunction are Associated with Increased Falls in Older Adults.

OBJECTIVE: This study aims to characterize the association between impairments in olfaction and balance, both of which are mediated in part by the cerebellum, and how this relates to prospective incidence of falls in a cohort of aging adults. METHODS: The Health ABC study was queried to identify 296 participants with data on both olfaction (measured using the 12-item Brief Smell Identification Test) and balance-related function (measured using the Romberg test). The relationship between olfaction and balance was investigated using multivariable logistic regression. Predictors of performance on a standing balance assessment and predictors of falls were studied. RESULTS: Of 296 participants, 52.7% had isolated olfactory dysfunction, 7.4% had isolated balance dysfunction, and 5.7% had dual dysfunction. Severe olfactory dysfunction was associated with increased odds of balance dysfunction when compared to those without olfactory dysfunction, even when adjusting for age, gender, race, education, BMI, smoking, diabetes, depression, and dementia (OR = 4.1, 95% CI [1.5, 13.7], p = 0.011). Dual sensory dysfunction was associated with worse performance on a standing balance assessment (ß = -22.8, 95% CI [-35.6, -10.1], p = 0.0005) and increased falls (ß = 1.5, 95% CI [1.0, 2.3], p = 0.037). CONCLUSION: This study highlights a unique relationship between olfaction and balance, and how dual dysfunction is associated with increased falls. With substantial implications of falls on morbidity and mortality in older adults, this novel relationship between olfaction and balance emphasizes a potentially shared mechanism between olfactory dysfunction and increased fall risk in older adults; however, further study is required to explore the novel relationship of olfaction with balance and future falls. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1964-1969, 2023.

Factors related to wellness and burnout in academic otolaryngology: A pre- and Post-COVID-19 analysis.

Objectives: Describe demographic and professional factors predictive of burnout in academic otolaryngology before and during the COVID-19 pandemic. Methods: In 2018 and 2020, cross-sectional surveys on physician wellness and burnout were distributed to faculty members of a single academic institution's otolaryngology department. Faculty were dichotomized into low and high burnout groups for 2018 (n = 8 high burnout, 19%) and 2020 (n = 11 high burnout, 37%). To identify protective factors against burnout, three semi-structured interviews were conducted with faculty that reported no burnout. Results: Forty-two participants (59%) in 2018 and 30 out of 49 participants (62%) in 2020 completed the survey. In multivariate analysis of 2018 survey data, full and associate professors had significantly lower odds of high burnout (OR 0.06, 95% CI 0.00-0.53; p = .03). Female gender was associated with increased in odds of high burnout (OR 15.55, 95% CI 1.86-231.74; p = .02). However, academic rank and gender did not remain independent predictors of high burnout in the 2020 survey. We identified significant differences in drivers of burnout brought on by the pandemic, including a shift from a myriad of work-related stressors in 2018 to a focus on patientcare and family obligations in 2020. Interview analysis identified three themes in faculty who reported no burnout: (1) focus on helping others, (2) happiness over compensation as currency, and (3) gratitude for the ability to have an impact. Conclusion: Approximately 20% of faculty reported high burnout before the pandemic, and this proportion nearly doubled during the pandemic. The risk factors and themes identified in this study may help academic otolaryngologists prevent burnout. Lay Summary: Factors driving burnout among academic otolaryngologists during the COVID-19 pandemic transitioned away from research, conferences, and work outside business hours toward family and patient responsibilities. Females report higher burnout and full professors report lower burnout. Level of evidence: III.

Outcomes after revision of Advanced Bionics Clarion 1.2 cochlear implants.

INTRODUCTION: Cochlear implant reimplantation (CIR) for external processor upgrade or device failure is becoming increasingly common as the population of cochlear implant recipients ages. Patients with Advanced Bionics (AB) Clarion 1.2 cochlear implants may undergo CIR for device age/failure or desired technology upgrade so that they may use newer external processors that have improved connectivity features. The objective of this study was to evaluate audiologic outcomes for patients who were initially implanted with an AB Clarion 1.2 internal device and underwent CIR for technology upgrade or device failure. METHODS: Retrospective chart review was performed at a single academic medical center for patients (pediatric and adult) with an AB Clarion 1.2 internal device who underwent CIR to a later generation AB internal device and had available audiologic data. RESULTS: Forty-eight individuals with a Clarion 1.2 implant underwent CIR. Pre- and post-CIR speech understanding did not change for AzBio (p-value = 0.11, mean change = 12.1%, 95% CI = -2.9-27.2%), CNCw (p-value = 0.74, mean change = -1%, 95% CI = -10.4-12.4%), or HINT (p-value = 0.12, mean change = 19.9%, 95% CI = -2.6-42.4%) scores. Pure-tone averages improved following CIR (p-value < 0.01, mean change = 4.3 dB, 95% CI = 1.5-7.1 dB). CONCLUSIONS: Revision of AB Clarion 1.2 cochlear implants does not significantly worsen audiologic outcomes and may improve hearing in some individuals, but individual patient-level outcomes are variable.

Hidradenitis Suppurativa Reddit Support Group: Finding New Meaning in Social Media During the COVID-19 Pandemic.

Hidradenitis suppurativa (HS) can significantly impact quality of life. Reddit allows users with common interests, like HS, to form a community and share information. This has become increasingly important with pandemic-related social isolation. We administered a survey from May 2021 to July 2021 to characterize patients with HS use of Reddit and social media more broadly before and during the COVID-19 pandemic. An analysis of a popular HS support page on Reddit from January 2019 to August 2021 was also conducted, analyzing subscribers over time. The rate of subscriber increase was higher before the pandemic. Of 42 patients contacted, 20 patients enrolled (90% female, mean age of 32.4 years) and 18 of the 20 fully completed the survey that was administered. Participants were stratified into two groups: online support group users (n = 8) and nonusers (n = 12). There were no differences in sex, age, education level, antidepressant usage, and overall social media usage between these groups. However, there was a difference in Hurley staging, with more than four times as many users reporting a Hurley III staging compared to nonusers (p = .003). Nonusers ranked the following as desired features of a social media group more frequently than current users: bandaging/dressing boils, living with HS, medical advice from professionals, causes of HS, and diet (P = .047, P = .043, P = .043, P = .047, and P = .013, respectively). This study demonstrates that online support group use is associated with HS of higher clinical severity. Based on the needs/expectations identified in this study, recommendations can be made to providers to help fill any lacunae in clinical care.

Costs and Readmissions Associated with Type A Aortic Dissections at High- and Low-Volume Centers.

BACKGROUND: Costs and readmissions associated with type A aortic dissection repairs are not well understood. We investigated statewide readmissions, costs, and outcomes associated with the surgical management of type A aortic dissection repairs at low- and high-volume centers. METHODS: We identified all adult type A aortic dissection patients who underwent operative repair in the Maryland Health Services Cost Review Commission's database (2012-2020). Hospitals were stratified into high- (top quartile of total repairs) or low-volume centers. RESULTS: Of the 249 patients included, 193 (77.5%) were treated at a high-volume center. Patients treated at high- and low-volume centers had no differences in age, sex, race, primary payer, or severity (all p > 0.5). High- compared to low-volume centers had a greater proportion of patients transferred in (71.5% vs. 17.9%, p < 0.001). High-volume centers also had longer lengths of stay (12 vs. 8 days, p < 0.001), similar inpatient mortality (13.0% vs. 16.1%, p = 0.6), and similar proportion of patients readmitted (54.9% vs. 51.8%, p = 0.7). High-volume centers had greater index admission costs ($114,859 vs. $72,090, p < 0.001) and similar readmission costs ($48,367 vs. $42,204, p = 0.5). At high-volume centers, transferred patients compared to direct admissions had greater severity of illness (p = 0.05), similar mortality (p = 0.53), and greater lengths of stay (p = 0.05). CONCLUSIONS: High-volume centers had a greater number of patients transferred from other institutions compared to low-volume centers. High-volume centers were associated with increased index admission resource utilization, with transfer patients having higher illness severity and greater resource utilization, yet similar mortality, compared to direct admission patients.

Virtual audiometric testing using smartphone mobile applications to detect hearing loss.

Objective: The COVID-19 pandemic drove the need for remote audiometric testing in the form of mobile applications for hearing assessment. This study sought to determine the accuracy of two smartphone-based hearing assessment applications, Mimi and uHear, against the gold standard of in-clinic audiometric testing. Methods: One hundred patients that presented to clinic for hearing assessment were randomly assigned to take either the Mimi or uHear hearing test alongside standard audiometric testing. Hearing thresholds measured using mobile applications were compared to those from audiometric testing to assess validity. Patient satisfaction was measured using a questionnaire that queried if the app met the user's need, if they would recommend the app to others, and how likely they were to use the app again. Results: Using Mimi, there were no differences in average hearing levels measured at any frequency when compared to standard audiometric testing. uHear overestimated hearing loss at 500 and 1000 Hz (p < .001 for both) by 5-10 Hz, and underestimated hearing loss at 6000 Hz (p < .001) by 5-10 Hz compared to standard audiometric testing. When stratified by level of hearing impairment, uHear overestimated impairment in those with normal hearing (p < .001). Mimi had higher sensitivity (0.971) and specificity (0.912) for hearing loss (defined as a pure tone average for 500, 1000, 2000, and 4000 Hz greater than 25 dB) than uHear (0.914 and 0.780, respectively). However, uHear outranked Mimi on all three questions in the satisfaction questionnaire (p = .01, p = .03, and p = .02, respectively). Conclusion: Mimi appears to be a reasonable substitute for standard audiometric testing when individuals cannot present to clinic for gold standard testing; however, the Mimi user experience can be improved. Level of evidence: Level II.

Heparin-Induced Thrombocytopenia After Cardiac Surgery-A Statewide Review of Health Care Utilization.

BACKGROUND: Despite its severe consequences, clinical and economic impacts of heparin-induced thrombocytopenia (HIT) after cardiac operations have not been well characterized. This study assessed statewide incidence, outcomes, and resource consumption associated with HIT after cardiac operations. METHODS: This was a retrospective investigation of cardiac surgery patients using the Maryland Health Services Cost Review Commission's database from 2012 to 2020. Health care costs, utilization, and outcomes for those who experienced postoperative HIT were compared with propensity score-matched controls. RESULTS: Of 33 583 cardiac surgery patients, 184 (0.55%) were diagnosed with postoperative HIT. Compared with non-HIT patients, HIT patients were significantly more likely to be in the oldest age group (>80 years; P < .001) and to have greater severity of illness at admission (P < .001). HIT was associated with a longer hospitalization (21 vs 7 days; P < .001), greater mortality (13.6% vs 2.3%; P < .001), and greater hospital charges ($123 160 vs $45 303; P < .001), even after propensity score matching. Readmission rates were not significantly different, however, and readmission hospital charges did not significantly differ between HIT and non-HIT patients. CONCLUSIONS: In addition to worse outcomes, HIT was associated with higher costs during index admissions but not during readmissions of cardiac surgery patients. Strategies to minimize HIT could yield better outcomes and reduced costs, particularly relevant for health care systems seeking improved value-based care while reducing unnecessary hospitalizations.

Vestibular therapy to reduce falls in people with Alzheimer's disease: study protocol for a pilot randomized controlled trial.

BACKGROUND: Falls are highly common in patients with Alzheimer's disease (AD); around two-thirds of AD patients fall annually. Fall events are major drivers of injury, early institutionalization, and shorter survival. Balance and mobility impairment are among the most important fall risk factors in AD patients. Vestibular therapy (VT) is an effective rehabilitation intervention in improving balance and fall risk through vestibular function, but not often used in AD. We want to evaluate the feasibility of using VT to reduce falls and improve balance function in patients with AD and drive use of an existing, potentially beneficial therapy in a patient population whose high level of vestibular deficits is currently unaddressed. METHODS: The proposed pilot clinical trial will be a parallel-group randomized controlled trial. Patients with a diagnosis of mild-moderate AD, age ≥ 60, and the presence of a caregiver will be recruited from the Johns Hopkins Memory and Alzheimer's Treatment Center. Eligible patients will be offered vestibular testing. Patients with vestibular loss will be offered participation in the VT trial. One-hundred AD patients with vestibular loss will be enrolled and randomized 1:1 into the control and intervention arms of the trial. All patients will undergo baseline balance and cognitive assessment, followed by 8 weeks of active control therapy or VT, consisting of ~25-min office sessions with a vestibular therapist. Patients will be tracked for falls and undergo follow-up balance and cognitive assessment at 8 and 52 weeks (1 year) to assess the potential short-term and longer-term effects, respectively, of VT on balance and cognition. The main outcomes of this trial are falls, balance (using the Berg Balance Scale and the Timed Up and Go test), and cognition (using the clock drawing test, the Card Rotations test, the Money Road Map test, and the triangle completion task). DISCUSSION: As the population ages and the number of individuals with AD in the US grows to a projected 14 million in 2050, managing falls in AD will continue to grow as a critical public health concern; this trial assesses feasibility of a potential solution. TRIAL REGISTRATION: ClinicalTrial.Gov identifier - NCT03799991 . Registered 01 August 2019.

Blood utilization and clinical outcomes in pancreatic surgery before and after implementation of patient blood management.

BACKGROUND: Over the past decade, patient blood management (PBM) programs have been developed to reduce allogeneic blood utilization. This is particularly important in pancreatic surgery, which has historically been associated with high transfusion requirements and morbid event rates. This study investigated blood utilization and clinical outcomes in pancreatic surgery before, during, and after the implementation of PBM. STUDY DESIGN AND METHODS: A total of 3482 pancreatic surgery patients were assessed in a 10-year retrospective cohort study (2009-2019) at a single academic center. Baseline patient characteristics, transfusion practices, postoperative morbidity (infectious, thrombotic, ischemic, respiratory, and renal complications), mortality, and length of stay were compared between patients in the pre-PBM (2009-2013), early-PBM (2014-2016), and mature-PBM (2017-2019) time periods. Multivariable analysis assessed the odds for composite morbidity/mortality. RESULTS: Comparing the mature-PBM to pre-PBM cohorts, transfused units per 100 discharged patients decreased by 53% for erythrocytes (155 to 73; P < .0001), 81% for plasma (79 to 15; P < .038), and 75% for platelets (10 to 2.5; P < .005). Clinical outcomes improved as well, with composite morbid event rates decreasing by more than 50%, from 236 in 1438 patients (16.4%) to 85 in 1145 patients (7.4%) (P < .0001). Mortality and length of stay remained unchanged. Compared to the pre-PBM time period, early-PBM was associated with a risk-adjusted decrease in composite morbidity/mortality (OR 0.73; 95% CI 0.57-0.93; P = .010), while mature-PBM demonstrated a further incremental decrease (OR 0.44; 95% CI 0.33-0.57; P < .0001). CONCLUSIONS: The implementation of PBM was associated with substantially decreased blood utilization in pancreatic surgery, without negatively impacting clinical outcomes.

Poor Cost Awareness Among Anesthesia Providers for Medications, Supplies, and Blood Products.

BACKGROUND: The objective of this study was to determine if anesthesia providers can accurately estimate the cost of commonly used medications, supplies, and blood products. METHODS: This study was conducted between April and June 2019 at an academic tertiary care hospital. Anesthesia providers (certified registered nurse anesthetists [CRNAs], residents, and fellows/attendings) were surveyed on their knowledge of the cost of commonly used therapies. Items were sorted into 12 categories: opioids, non-opioid analgesia, vasopressors, hypertension medications, antibiotics, neuromuscular blockers, reversals, anesthetics, supplies, kits, blood products, and blood-related products. Estimates were considered to be accurate if the median cost differed from the average wholesale price by < 25%, moderately inaccurate if between 25% and 50%, and severely inaccurate if by > 50%. RESULTS: A total of 107 surveys (CRNAs: 25, residents: 36, fellows/attendings: 46) were returned. The percentage of total items accurately estimated for cost was low (22% for all providers), and was not different between provider types (27% for CRNAs, 23% for residents, 20% for fellows/attendings; p = 0.69). The percentage of items with severe inaccuracies in cost estimation was high and was not different between provider types (56% for CRNAs, 60% for residents, 50% for fellows/attendings; p = 0.53). Rates of under- and overestimation varied widely, with greatest underestimation for vasopressors and blood-related products, and greatest overestimation for non-opioid analgesia and antibiotics. Low- and high-cost category items tended to be overestimated and underestimated, respectively (p < 0.0001). CONCLUSION: The majority of anesthesia providers have poor knowledge of cost. These findings suggest that cost awareness interventions may be necessary for promoting high-value health care.

Blood Utilization and Clinical Outcomes in Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: Patients requiring extracorporeal membrane oxygenation (ECMO) support are critically ill and have substantial transfusion requirements, which convey both risks and benefits. A retrospective analysis was conducted to assess the association between blood component administration and adverse outcomes in adult, pediatric, and neonatal ECMO patients. METHODS: We evaluated 217 ECMO patients at a single center hospitalized between January 2009 and June 2016. Three cohorts (88 adult, 57 pediatric, and 72 neonatal patients) were included for assessment of patient characteristics, blood utilization, and clinical outcomes. Univariable and multivariable analyses were used to assess the association between transfusions and clinical outcomes (primary outcome: mortality and secondary outcomes: morbid events). The analysis included the main exposure of interest (total number of blood component units transfused) and potential confounding variables (age group cohort, case mix index, sex, ECMO mode and duration, and primary ECMO indication). RESULTS: After adjustment for confounders, with each additional blood component unit transfused, there was an estimated increase in odds for mortality by 1% (odds ratio [OR] = 1.01; 95% confidence interval [CI], 1.00-1.02; P = .013) and an increase in odds for thrombotic events by 1% (OR = 1.01; 95% CI, 1.00-1.02; P = .007). Mortality was higher in the adult (57 of 88; 64.8%) and pediatric (37 of 57; 64.9%) than in the neonatal cohort (19 of 72; 26.4%) (P < .0001). Median total blood components transfused per day followed a similar pattern for the adult (2.3 units; interquartile range [IQR] = 0.8-7.0), pediatric (2.9 units; IQR = 1.1-10), and neonatal (1.0 units; IQR = 0.7-1.6) cohorts (P < .0001). Over the entire hospitalization, the total median blood components transfused was highest in the neonatal (41 units; IQR = 24-94) and pediatric (41 units; IQR = 17-113) compared to the adult (30 units; IQR = 9-58) cohort (P = .007). There was no significant interaction between total units transfused over the hospital stay and age cohort for mortality (P = .35). CONCLUSIONS: Given the association between transfusion and adverse outcomes, effective blood management strategies may be beneficial in ECMO patients.