Structural Racism as a Contributor to Lung Cancer Incidence and Mortality Rates Among Black Populations in the United States.

BACKGROUND: Although racial disparities in lung cancer incidence and mortality have diminished in recent years, lung cancer remains the second most diagnosed cancer among US Black populations. Many factors contributing to disparities in lung cancer are rooted in structural racism. To quantify this relationship, we examined associations between a multidimensional measure of county-level structural racism and county lung cancer incidence and mortality rates among Black populations, while accounting for county levels of environmental quality. METHODS: We merged 2016-2020 data from the United States Cancer Statistics Data Visualization Tool, a pre-existing county-level structural racism index, the Environmental Protection Agency's 2006-2010 Environmental Quality Index (EQI), 2023 County Health Rankings, and the 2021 United States Census American Community Survey. We conducted multivariable linear regressions to examine associations between county-level structural racism and county-level lung cancer incidence and mortality rates. RESULTS: Among Black males and females, each standard deviation increase in county-level structural racism score was associated with an increase in county-level lung cancer incidence of 6.4 (95% CI: 4.4, 8.5) cases per 100,000 and an increase of 3.3 (95% CI: 2.0, 4.6) lung cancer deaths per 100,000. When examining these associations stratified by sex, larger associations between structural racism and lung cancer rates were observed among Black male populations than among Black females. CONCLUSION: Structural racism contributes to both the number of new lung cancer cases and the number of deaths caused by lung cancer among Black populations. Those aiming to reduce lung cancer cases and deaths should consider addressing racism as a root-cause.

The Association of Oncology Provider Density With Black-White Disparities in Cancer Mortality in US Counties.

BACKGROUND: Black-White racial disparities in cancer mortality are well-documented in the US. Given the estimated shortage of oncologists over the next decade, understanding how access to oncology care might influence cancer disparities is of considerable importance. We aim to examine the association between oncology provider density in a county and Black-White cancer mortality disparities. METHODS: An ecological study of 1048 US counties was performed. Oncology provider density was estimated using the 2013 National Plan and Provider Enumeration System data. Black:White cancer mortality ratio was calculated using 2014-2018 age-standardized cancer mortality rates from State Cancer Profiles. Linear regression with covariate adjustment was constructed to assess the association of provider density with (1) Black:White cancer mortality ratio, and (2) cancer mortality rates overall, and separately among Black and White persons. RESULTS: The mean Black:White cancer mortality ratio was 1.12, indicating that cancer mortality rate among Black persons was on average 12% higher than that among White persons. Oncology provider density was significantly associated with greater cancer mortality disparities: every 5 additional oncology providers per 100 000 in a county was associated with a .02 increase in the Black:White cancer mortality ratio (95% CI: .007 to .03); however, the unexpected finding may be explained by further analysis showing that the relationship between oncology provider density and cancer mortality was different by race group. Every 5 additional oncologists per 100 000 was associated with a 1.6 decrease per 100 000 in cancer mortality rates among White persons (95% CI: -3.0 to -.2), whereas oncology provider density was not associated with cancer mortality among Black persons. CONCLUSION: Greater oncology provider density was associated with significantly lower cancer mortality among White persons, but not among Black persons. Higher oncology provider density alone may not resolve cancer mortality disparities, thus attention to ensuring equitable care is critical.

Our study provides timely information to address the growing concern about the need to increase oncology supply and the impact it might have on racial disparities in cancer outcomes. This analysis of counties across the US is the first study to estimate the association of oncology provider density with Black-White racial disparities in cancer mortality. We show that having more oncology providers in a county is associated with significantly lower cancer mortality among the White population, but is not associated with cancer mortality among the Black population, thereby leading to a disparity. Our findings suggest that having more oncology providers alone may be insufficient to overcome existing disadvantages for Black patients to access and use high-quality cancer care. These findings have important implications for addressing racial disparities in cancer outcomes that are persistent and well-documented in the US.

Links of Previous Incarceration With Geriatric Syndromes and Chronic Health Conditions Among Older Adults in the United States.

BACKGROUND: This study investigated the association between previous incarceration and various geriatric and chronic health conditions among adults 50 and older in the United States. METHODS: Data came from the National Longitudinal Study of Adolescent to Adult Health-Parent Study (AHPS) collected in 2015-2017, including 2 007 individuals who participated in the parent study (Parent Sample) and 976 individuals who participated in the spouse/partner study (Spouse/Partner Sample). Multiple logistic regression was used to investigate the relationship between previous incarceration and geriatric syndromes (dementia, difficulty walking, difficulty seeing, difficulty with activities of daily living) and chronic health conditions (self-reported poor/fair health, diagnosis of cancer, hypertension, diabetes, heart disease, stroke, chronic lung disease, depression, and alcohol use [4 or more drinks per week]). RESULTS: In adjusted analyses, respondents with previous incarceration in the AHPS had significantly higher odds of reporting difficulty walking, activities of daily living difficulty, cancer diagnosis, depression diagnosis, and chronic lung disease (adjusted odds ratios [aORs] = 2.21-2.95). Respondents in the AHPS spouse/partner study reported higher odds of difficulty seeing, cancer, depression, chronic lung disease, and heavy alcohol use (aORs = 1.02-2.15). CONCLUSIONS: Previous incarceration may have an adverse impact on healthy aging. Findings highlight the importance of addressing the enduring health impacts of incarceration, particularly as individual transition into older adulthood.

Auditory brainstem implantation: surgical experience and audiometric outcomes in the pediatric population.

OBJECTIVE: Pediatric data regarding treatment via an auditory brainstem implant (ABI) remains sparse. The authors aimed to describe their experience at their institution and to delineate associated demographic data, audiometric outcomes, and surgical parameters. METHODS: An IRB-approved, retrospective chart review was conducted among the authors' pediatric patients who had undergone auditory brainstem implantation between 2012 and 2021. Demographic information including sex, age, race, coexisting syndrome(s), history of cochlear implant placement, average duration of implant use, and follow-up outcomes were collected. Surgical parameters collected included approach, intraoperative findings, number of electrodes activated, and complications. RESULTS: A total of 19 pediatric patients had an ABI placed at the authors' institution, with a mean age at surgery of 4.7 years (range 1.5-17.8 years). A total of 17 patients (89.5%) had bilateral cochlear nerve aplasia/dysplasia, 1 (5.3%) had unilateral cochlear nerve aplasia/dysplasia, and 1 (5.3%) had a hypoplastic cochlea with ossification. A total of 11 patients (57.9%) had a history of cochlear implants that were ineffective and required removal. The mean length of implant use was 5.31 years (0.25-10 years). Two patients (10.5%) experienced CSF-related complications requiring further surgical intervention. The most recent audiometric outcomes demonstrated that 15 patients (78.9%) showed improvement in their hearing ability: 5 with sound/speech awareness, 5 able to discriminate among speech and environmental sounds, and 5 able to understand common phrases/conversation without lip reading. Nine patients (47.4%) are in a school for the deaf and 7 (36.8%) are in a mainstream school with support. CONCLUSIONS: The authors' surgical experience with a multidisciplinary team demonstrates that the retrosigmoid approach for ABI placement in children with inner ear pathologies and severe sensorineural hearing loss is a safe and effective treatment modality. Audiometric outcome data showed that nearly 79% of these patients had an improvement in their environmental and speech awareness. Further multicenter collaborations are necessary to improve these outcomes and potentially standardize/enhance electrode placement.

Salvage Microsurgery Following Failed Primary Radiosurgery in Sporadic Vestibular Schwannoma.

Importance: Management of sporadic vestibular schwannoma with radiosurgery is becoming increasingly common globally; however, limited data currently characterize patient outcomes in the setting of microsurgical salvage for radiosurgical failure. Objective: To describe the clinical outcomes of salvage microsurgery following failed primary stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) among patients with sporadic vestibular schwannoma. Design, Setting, and Participants: This was a cohort study of adults (≥18 years old) with sporadic vestibular schwannoma who underwent salvage microsurgery following failed primary SRS/FSRT in 7 vestibular schwannoma treatment centers across the US and Norway. Data collection was performed between July 2022 and January 2023, with data analysis performed between January and July 2023. Exposure: Salvage microsurgical tumor resection. Main Outcomes and Measures: Composite outcome of undergoing less than gross total resection (GTR) or experiencing long-term facial paresis. Results: Among 126 patients, the median (IQR) age at time of salvage microsurgery was 62 (53-70) years, 69 (55%) were female, and 113 of 117 (97%) had tumors that extended into the cerebellopontine angle at time of salvage. Of 125 patients, 96 (76%) underwent primary gamma knife SRS, while 24 (19%) underwent linear accelerator-based SRS; the remaining patients underwent FSRT using other modalities. Postoperative cerebrospinal fluid leak was seen in 15 of 126 patients (12%), hydrocephalus in 8 (6%), symptomatic stroke in 7 (6%), and meningitis in 2 (2%). Each 1-mm increase in cerebellopontine angle tumor size was associated with a 13% increased likelihood of foregoing GTR (64 of 102 patients [63%]) or long-term postoperative House-Brackmann grade higher than I (48 of 102 patients [47%]) (odds ratio, 1.13; 95% CI, 1.04-1.23). Following salvage microsurgery, tumor growth-free survival rates at 1, 3, and 5 years were 97% (95% CI, 94%-100%), 93% (95% CI, 87%-99%), and 91% (95% CI, 84%-98%), respectively. Conclusions: In this cohort study, more than half of patients who received salvage microsurgery following primary SRS/FSRT underwent less than GTR or experienced some degree of facial paresis long term. These data suggest that the cumulative risk of developing facial paresis following primary SRS/FSRT by the end of the patient's journey with treatment approximates 2.5% to 7.5% when using published primary SRS/FSRT long-term tumor control rates.

Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.

BACKGROUND: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. METHODS: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. RESULTS: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. CONCLUSIONS: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.

Measuring Racial Differences in Obesity Risk Factors in Non-Hispanic Black and White Men Aged 20 Years or Older.

Obesity prevalence in the United States has increased drastically in the last two decades. Racial differences in obesity have emerged with the increase in obesity, with temporal trends because of individual, socioeconomic, and environmental factors, eating behaviors, lack of exercise, etc., raising questions about understanding the mechanisms driving these racial differences in the prevalence of obesity among non-Hispanic Black (NHB) and non-Hispanic White (NHW) men. Although many studies have measured obesity using body mass index (BMI), little is known about waist circumference (WC). This study examines variations in obesity among NHW and NHB using BMI and WC. We used National Health and Nutrition Examination Surveys (1999-2016) with a sample of 9,000 NHW and 3,913 NHB men aged 20 years or older. To estimate the association between the prevalence of obesity (BMI ≥30) and race, we applied modified Poisson regression; to explore and decompose racial differences, we used Oaxaca-Blinder decomposition (OBD). We found that NHW had higher abdominal obesity (WC ≥102) than NHB, but NHB were more likely to be obese (BMI ≥30) during most years, with some fluctuations. Modified Poisson regression showed that NHB had a higher prevalence of obesity (prevalence ratio [PR]: 1.11, 95% confidence interval [CI] = [1.04, 1.18]) but lower abdominal obesity (PR: 0.845; 95% CI = [0.801, 0.892]) than NHW. OBD showed that age, access to health care, smoking, and drinking contributed to the differences in abdominal obesity. The study identifies a significant increase in obesity among men over the last two decades; generalized obesity (based on BMI) was more problematic for NHB men, but abdominal obesity was more problematic for NHW men.

Rationale for the Development of a Novel Clinical Grading Scale for Postoperative Facial Nerve Function: Results of a Multidisciplinary International Working Group.

OBJECTIVE: The objective of the current study was to present the results of an international working group survey identifying perceived limitations of existing facial nerve grading scales to inform the development of a novel grading scale for assessing early postoperative facial paralysis that incorporates regional scoring and is anchored in recovery prognosis and risk of associated complications. STUDY DESIGN: Survey. SETTING: A working group of 48 multidisciplinary clinicians with expertise in skull base, cerebellopontine angle, temporal bone, or parotid gland surgery. RESULTS: House-Brackmann grade is the most widely used system to assess facial nerve function among working group members (81%), although more than half (54%) agreed that the system they currently use does not adequately estimate the risk of associated complications, such as corneal injury, and confidence in interrater and intrarater reliability is generally low. Simplicity was ranked as the most important attribute of a novel postoperative facial nerve grading system to increase the likelihood of adoption, followed by reliability and accuracy. There was widespread consensus (91%) that the eye is the most critical facial region to focus on in the early postoperative setting. CONCLUSIONS: Members were invited to submit proposed grading systems in alignment with the objectives of the working group for subsequent validation. From these data, we plan to develop a simple, clinically anchored, and reproducible staging system with regional scoring for assessing early postoperative facial nerve function after surgery of the skull base, cerebellopontine angle, temporal bone, or parotid gland.

Associations of polygenic risk scores for smoking heaviness and lifetime cannabis use with tobacco and cannabis co-use trajectories among African Americans.

BACKGROUND: We aimed to identify distinct trajectories of tobacco, cannabis, and their co-use among African Americans, and to investigate whether these patterns were associated with polygenic risk scores (PRS) for tobacco and cannabis use. METHOD: Participants (N=428 participants; 50.9% male) were initially recruited for an elementary school-based prevention in a Mid-Atlantic city when they were in first grade. From ages 14-26, participants reported on their frequency of tobacco and cannabis use in the past year during annual assessments. DNA was collected from participants at age 21. PRS for smoking heaviness (i.e., cigarettes per day) and lifetime cannabis use were created based on genome-wide association study results derived from Liu et al. (2019) and Pasman et al. (2018), respectively. RESULTS: We identified five distinct trajectories of tobacco and cannabis co-use, including (1) Low Tobacco and Cannabis Use, (2) Adolescent Limited Tobacco and Cannabis Use, (3) Experimental Cannabis, Young Adult Increasing Tobacco, (4) Experimental Tobacco, Young Adult Increasing Cannabis, and (5) High, Chronic Tobacco and Cannabis Use. Compared to the Low Tobacco and Cannabis Use subgroup, individuals in the High, Chronic Tobacco and Cannabis Use subgroup had greater PRS for smoking heaviness, and individuals in the Experimental Cannabis, Young Adult Increasing Tobacco subgroup had higher PRS for lifetime cannabis use. CONCLUSIONS: Polygenic risk for lifetime cannabis use and smoking heaviness is associated with the developmental progression of tobacco and cannabis co-use among African Americans, furthering knowledge on the etiology of co-use in this population.

Stratifying Risk of Future Growth Among Sporadic Vestibular Schwannomas.

OBJECTIVE: In certain cases, clinicians may consider continued observation of a vestibular schwannoma after initial growth is detected. The aim of the current work was to determine if patients with growing sporadic vestibular schwannomas could be stratified by the likelihood of subsequent growth based on initial growth behavior. STUDY DESIGN: Slice-by-slice volumetric tumor measurements from 3,505 serial magnetic resonance imaging studies were analyzed from 952 consecutively treated patients. SETTING: Three tertiary-referral centers. PATIENTS: Adults with sporadic vestibular schwannoma. INTERVENTIONS: Wait-and-scan. MAIN OUTCOME MEASURES: Composite end point of subsequent growth- or treatment-free survival rates, where growth is defined as an additional increase of at least 20% in tumor volume from the volume at the time of initial growth. RESULTS: Among 405 patients who elected continued observation despite documented growth, stratification, of volumetric growth rate into less than 25% (reference: n = 107), 25 to less than 50% (hazard ratio [HR], 1.39; p = 0.06; n = 96), 50 to less than 100% (HR, 1.71; p = 0.002; n = 112), and at least 100% (HR, 2.01; p < 0.001; n = 90) change per year predicted the likelihood of future growth or treatment. Subsequent growth- or treatment-free survival rates (95% confidence interval) at year 5 after detection of initial growth were 31% (21-44%) for those with less than 25% growth per year, 18% (10-32%) for those with 25 to less than 50%, 15% (9-26%) for those with 50 to less than 100%, and 6% (2-16%) for those with at least 100%. Neither patient age ( p = 0.15) nor tumor volume at diagnosis ( p = 0.95) significantly differed across stratification groups. CONCLUSIONS: At the time of diagnosis, clinical features cannot consistently predict which tumors will ultimately display aggressive behavior. Stratification by volumetric growth rate at the time of initial growth results in a stepwise progression of increasing likelihood of subsequent growth. When considering continued observation after initial growth detection, almost 95% of patients who have tumors that double in volume between diagnosis and the first detection of growth demonstrate further tumor growth or undergo treatment if observed to 5 years.

The Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D) at the Spallation Neutron Source (invited).

The Oak Ridge National Laboratory is planning to build the Second Target Station (STS) at the Spallation Neutron Source (SNS). STS will host a suite of novel instruments that complement the First Target Station's beamline capabilities by offering an increased flux for cold neutrons and a broader wavelength bandwidth. A novel neutron imaging beamline, named the Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D), is among the first eight instruments that will be commissioned at STS as part of the construction project. CUPI2D is designed for a broad range of neutron imaging scientific applications, such as energy storage and conversion (batteries and fuel cells), materials science and engineering (additive manufacturing, superalloys, and archaeometry), nuclear materials (novel cladding materials, nuclear fuel, and moderators), cementitious materials, biology/medical/dental applications (regenerative medicine and cancer), and life sciences (plant-soil interactions and nutrient dynamics). The innovation of this instrument lies in the utilization of a high flux of wavelength-separated cold neutrons to perform real time in situ neutron grating interferometry and Bragg edge imaging-with a wavelength resolution of δλ/λ ≈ 0.3%-simultaneously when required, across a broad range of length and time scales. This manuscript briefly describes the science enabled at CUPI2D based on its unique capabilities. The preliminary beamline performance, a design concept, and future development requirements are also presented.

Bilateral cochlear implantation after immunotherapy-related profound hearing loss: A case report.

OBJECTIVES: Immune-checkpoint inhibitors (ICI) are being utilized with increasing frequency and may be linked to neurologic and audiovestibular toxicities. This report aimed to describe a case of ICI-induced sensorineural hearing loss ultimately requiring bilateral cochlear implantation. METHODS: A 42-year-old female with stage IV metastatic melanoma of the perianal skin was treated with ipilimumab (blocker of cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) and nivolumab (anti-programmed cell death protein 1 [PD1]). After 21 weeks of therapy, she developed sudden vertigo and bilateral hearing loss. A full workup including MRI and lumbar puncture ruled out intracranial parenchymal metastases, leptomeningeal metastases, stroke and intracranial infection. ICI-associated aseptic meningoencephalitis was therefore diagnosed. The patient received systemic steroids as well as intratympanic steroids, which temporarily improved hearing, but eventually developed permanent, bilateral profound sensorineural hearing loss. RESULTS: The patient received bilateral cochlear implants and has demonstrated good performance one year after implantation. DISCUSSION: ICI are being increasingly used to treat a variety of advanced malignancies. This is the first report of bilateral cochlear implants in the context of profound hearing loss after an immunotherapy induced meningoencephalitis. CONCLUSION: ICI carries the risk of potential ototoxicity, including profound SNHL as depicted in our case. Cochlear implantation proved to be beneficial and may be considered in patients with ICI-related hearing loss.

Cecal Endometriosis Presenting as Hematochezia in a Postmenopausal Female.

Our report highlights the diagnosis of cecal endometriosis as a unique cause of hematochezia in a postmenopausal female. Cecal endometriosis manifesting as intermittent hematochezia and abdominal pain is uncommon but requires prompt clinical diagnosis and management. We report a case of cecal endometriosis causing hematochezia and subsequent syncope, which prompted the patient's admission to the emergency department. In our patient, a diagnosis of cecal endometriosis was made after a colonoscopy, with multiple biopsies confirming the presence of endometrial tissue embedded in the cecum. We aim to bring awareness of cecal endometriosis presenting as hematochezia in a postmenopausal woman with a history of abdominal pain. This case highlights intestinal endometriosis as a differential diagnosis to be considered in women, regardless of age, with intermittent hematochezia and abdominal pain.

The National Conference on Health Disparities Student Research Forum.

The annual National Conference on Health Disparities (NCHD) was launched in 2000. It unites health professionals, researchers, community leaders, and government officials, and is a catalyzing force in developing policies, research interventions, and programs that address prevention, social determinants, health disparities, and health equity. The NCHD Student Research Forum (SRF) was established in 2011 at the Medical University of South Carolina to build high-quality biomedical research presentation capacity in primarily underrepresented undergraduate and graduate/professional students. This paper describes the unique research training and professional development aspects of the NCHD SRF. These include guidance in abstract development, a webinar on presentation techniques and methods, a vibrant student-centric conference, and professional development workshops on finding a mentor and locating scholarship/fellowship funding, networking, and strategies for handling ethical issues in research with mentors. Between 2011 and 2018, 400 undergraduate and graduate/professional students participated in the NCHD SRF. Most students were women (80.5%). Approximately half were African American or black (52.3%), 18.0% were white, and 21.3% were of Hispanic/Latinx ethnicity. The NCHD SRF is unique in several ways. First, it provides detailed instructions on developing a scientific abstract, including content area examples. Second, it establishes a mandatory pre-conference training webinar demonstrating how to prepare a scientific poster. Third, it works with the research mentors, faculty advisors, department chairs, and deans to help identify potential sources of travel funding for students with accepted abstracts. These features make the NCHD SRF different from many other conferences focused on students' scientific presentations.

Discovery of a Series of Potent, Selective, and Orally Bioavailable Nucleoside Inhibitors of CD73 That Demonstrates In Vivo Antitumor Activity.

CD73 (ecto-5'-nucleotidase) has emerged as an attractive target for cancer immunotherapy of many cancers. CD73 catalyzes the hydrolysis of adenosine monophosphate (AMP) into highly immunosuppressive adenosine that plays a critical role in tumor progression. Herein, we report our efforts in developing orally bioavailable and highly potent small-molecule CD73 inhibitors from the reported hit molecule 2 to lead molecule 20 and then finally to compound 49. Compound 49 was able to reverse AMP-mediated suppression of CD8+ T cells and completely inhibited CD73 activity in serum samples from various cancer patients. In preclinical in vivo studies, orally administered 49 showed a robust dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship that correlated with efficacy. Compound 49 also demonstrated the expected immune-mediated antitumor mechanism of action and was efficacious upon oral administration not only as a single agent but also in combination with either chemotherapeutics or checkpoint inhibitor in the mouse tumor model.

Slim Modiolar Electrode Placement in Candidates for Electroacoustic Stimulation.

OBJECTIVES: To determine rates of hearing preservation and performance in patients who met candidacy for electroacoustic stimulation (EAS) and were implanted with a slim modiolar electrode (CI532 or CI632). DESIGN: Adult patients meeting Food and Drug Administration criteria for electroacoustic stimulation (preoperative low-frequency pure-tone average [LFPTA] less than 60 dB at 125, 250, and 500 Hz and monosyllabic word scores between 10% and 60% in the ear to be implanted), who received a slim modiolar electrode were included. Main outcome measures included rates of hearing preservation, defined as a LFPTA ≤80 dB at 125, 250, and 500 Hz, as well as postoperative low-frequency pure-tone threshold shifts, consonant-Nucleus-Consonant (CNC) word scores and AzBio sentences in noise scores. RESULTS: Forty-six patients met inclusion criteria during a 4-year period. Mean (standard deviation) preoperative LFPTA was 34.5 (13.0) dB, and 71.7% had preserved hearing at initial activation. The mean LFPTA shift in patients who preserved hearing at initial activation was 19.7 (14.6) dB, compared with 62.6 (17.7) dB in patients who did not preserve hearing as per our definition. Perioperative steroid use was not different in patients with and without preserved hearing (X 2 (1, N = 46) = 0.19, p = .67, V = 0.06). One year after surgery, 57% of patients had a decline in LFPTA >80 dB and were no longer considered candidates for EAS, with 34.7% still retaining low-frequency thresholds ≤80 dB. CNC word scores at 1 year were 69.9% and 61.4% among individuals with and without preserved low-frequency hearing respectively, measured in their CI ear alone, in their regular listening condition of EAS or electric only ( t (32) = 1.13, p = 0.27, d = 0.39, 95% CI = -6.51, 22.86). Device use time did not differ between groups. Among adults with preserved residual hearing at 1 year (n = 16), 44% used EAS, although there was no significant difference in performance between EAS users and nonusers with preserved hearing. Loss of residual hearing over time did not result in a decline in speech perception performance. CONCLUSION: The present study demonstrated favorable early rates of hearing preservation with a slim modiolar array. Performance was not significantly different in individuals with and without preserved low-frequency acoustic hearing, independent of EAS use. Compared with reports of short electrode use, the loss of residual hearing in patients implanted with this array did not impact speech perception performance.

HiRes ultra series cochlear implant field recall: failure rates and early outcomes.

OBJECTIVE: Evaluate rates of Advanced Bionics Ultra 3D/Ultra cochlear implant failure in the setting of a worldwide device recall and report surgical and auditory outcomes after revision. METHODS: Retrospective chart review was performed for adult and pediatric patients implanted with at risk devices at our center from 2016 to 2020. Device failure rates, surgical, and auditory outcomes were recorded and analyzed. RESULTS: Of 113 at-risk devices, 20 devices (17.7%) in 18 patients (two bilaterally implanted) were identified as failures. All devices were with mid-scala electrodes. Eleven patients (61.1%) were children and 7 (38.9%) adults. Twelve patients were found to have failing devices after reporting subjective performance decline; the remainder were prompted by manufacturer notification. All were revised, with the majority (83.3%) choosing the same manufacturer. All had uncomplicated original and revision insertions. Among adults, average word scores on the revised side were stable pre- to post-revision (P = 0.95). DISCUSSION: Patients with device failure due to this field action performed well after revision implantation. Patients with bilateral at-risk devices but evidence of unilateral failure may elect to undergo simultaneous empiric revision of the contralateral device. Three patients who elected to change device manufacturers on revision have variable results that require further investigation. CONCLUSIONS: Patients requiring revision for a device field action overall perform well. At-risk devices continue to require monitoring as a growing number are likely to fail over time.

Monitoring Cochlear Health With Intracochlear Electrocochleography During Cochlear Implantation: Findings From an International Clinical Investigation.

OBJECTIVES: Electrocochleography (ECochG) is emerging as a tool for monitoring cochlear function during cochlear implant (CI) surgery. ECochG may be recorded directly from electrodes on the implant array intraoperatively. For low-frequency stimulation, its amplitude tends to rise or may plateau as the electrode is inserted. The aim of this study was to explore whether compromise of the ECochG signal, defined as a fall in its amplitude of 30% or more during insertion, whether transient or permanent, is associated with poorer postoperative acoustic hearing, and to examine how preoperative hearing levels may influence the ability to record ECochG. The specific hypotheses tested were threefold: (a) deterioration in the pure-tone average of low-frequency hearing at the first postoperative follow-up interval (follow-up visit 1 [FUV1], 4 to 6 weeks) will be associated with compromise of the cochlear microphonic (CM) amplitude during electrode insertion (primary hypothesis); (b) an association is observed at the second postoperative follow-up interval (FUV2, 3 months) (secondary hypothesis 1); and (c) the CM response will be recorded earlier during electrode array insertion when the preoperative high-frequency hearing is better (secondary hypothesis 2). DESIGN: International, multi-site prospective, observational, between groups design, targeting 41 adult participants in each of two groups, (compromised CM versus preserved CM). Adult CI candidates who were scheduled to receive a Cochlear Nucleus CI with a Slim Straight or a Slim Modiolar electrode array and had a preoperative audiometric low-frequency average thresholds of ≤80 dB HL at 500, 750, and 1000 Hz in the ear to be implanted, were recruited from eight international implant sites. Pure tone audiometry was measured preoperatively and at postoperative visits (FUV1 and follow-up visit 2 [FUV2]). ECochG was measured during and immediately after the implantation of the array. RESULTS: From a total of 78 enrolled individuals (80 ears), 77 participants (79 ears) underwent surgery. Due to protocol deviations, 18 ears (23%) were excluded. Of the 61 ears with ECochG responses, amplitudes were < 1 µV throughout implantation for 18 ears (23%) and deemed "unclear" for classification. EcochG responses >1 µV in 43 ears (55%) were stable throughout implantation for 8 ears and compromised in 35 ears. For the primary endpoint at FUV1, 7/41 ears (17%) with preserved CM had a median hearing loss of 12.6 dB versus 34/41 ears (83%) with compromised CM and a median hearing loss of 26.9 dB ( p < 0.014). In assessing the practicalities of measuring intraoperative ECochG, the presence of a measurable CM (>1 µV) during implantation was dependent on preoperative, low-frequency thresholds, particularly at the stimulus frequency (0.5 kHz). High-frequency, preoperative thresholds were also associated with a measurable CM > 1 µV during surgery. CONCLUSIONS: Our data shows that CM drops occurring during electrode insertion were correlated with significantly poorer hearing preservation postoperatively compared to CMs that remained stable throughout the electrode insertion. The practicality of measuring ECochG in a large cohort is discussed, regarding the suggested optimal preoperative low-frequency hearing levels ( < 80 dB HL) considered necessary to obtain a CM signal >1 µV.

Associations Between Objectively Measured Sleep and Cognition: Main Effects and Interactions With Race in Adults Aged ≥50 Years.

BACKGROUND: This study examined associations of actigraphy-estimated sleep parameters with concurrent and future cognitive performance in adults aged ≥ 50 years and explored interactions with race. METHODS: Participants were 435 cognitively normal adults in the Baltimore Longitudinal Study of Aging who completed wrist actigraphy at baseline (mean = 6.6 nights) and underwent longitudinal testing of memory, attention, executive function, language, and visuospatial ability. On average, participants with follow-up data were followed for 3.1 years. Primary predictors were baseline mean total sleep time, sleep onset latency, sleep efficiency (SE), and wake after sleep onset (WASO). Fully adjusted linear mixed-effects models included demographics, baseline health-related characteristics, smoking status, sleep medication use, APOE e4 carrier status, and interactions of each covariate with time. RESULTS: In adjusted models, higher SE (per 10%; B = 0.11, p = .012) and lower WASO (per 30 minutes; B = -0.12, p = .007) were associated with better memory cross-sectionally. In contrast, higher SE was associated with greater visuospatial ability decline longitudinally (B = -0.02, p = .004). Greater WASO was associated with poorer visuospatial ability cross-sectionally (B = -0.09, p = .019) but slower declines in visuospatial abilities longitudinally (B = 0.02, p = .002). Several sleep-cognition cross-sectional and longitudinal associations were stronger in, or limited to, Black participants (compared to White participants). CONCLUSIONS: This study suggests cross-sectional sleep-cognition associations differ across distinct objective sleep parameters and cognitive domains. This study also provides preliminary evidence for racial differences across some sleep-cognition relationships. Unexpected directions of associations between baseline sleep and cognitive performance over time may be attributable to the significant proportion of participants without follow-up data and require further investigation.

A randomized, double-blind, placebo-controlled, cross-over trial to evaluate the effect of EstroSense® on 2-hydroxyestrone:16α-hydroxyestrone ratio in premenopausal women.

OBJECTIVES: Some estrogen metabolites are associated with increased breast cancer risk, while others are protective. Research efforts have focused on modifiable factors, including bioactive compounds found in food or supplements, promoting estrogen profiles with anti-cancer properties. EstroSense® is a nutraceutical product with bioactive compounds, including Indole-3-carbinol and green-tea catechins, which may favourably affect estrogen profiles. This study was conducted to determine if EstroSense use, compared to placebo, promotes a higher urinary 2-hydroxyestrone:16α-hydroxyestrone ratio (2-OHE1:16α-OHE1), a biomarker associated with a lowered risk of breast cancer. METHODS: A total of 148 premenopausal women were recruited from British Columbia, Canada to participate in a randomized, double-blind, cross-over, multicentre, placebo-controlled study in which women were randomized to a treatment sequence that consisted of either EstroSense®, followed by placebo or vice-versa. The women were instructed to consume three capsules per day of EstroSense® or the placebo for three menstrual cycles (∼12 weeks). The primary outcome was the measurement of 2-OHE1:16α-OHE1 in casual samples at baseline and after each treatment phase. RESULTS: After 12 weeks of intervention, the mean (95% CI) urinary 2-OHE1:16α-OHE1 was 4.55 (2.69, 6.42) (p<0.001) higher following EstroSense than placebo adjusted for baseline values. CONCLUSIONS: EstroSense use led to markedly higher urinary 2-OHE1:16α-OHE1 than the placebo, a biomarker associated with a lower risk of breast cancer. REGISTRATION: http://clinicaltrials.gov (NCT02385916).