Comparing Satisfaction Among Providers Treating Both Pediatric and Adult Otolaryngology Patients.

Objective: Although pediatric otolaryngology providers are reported to garner lower patient satisfaction than adults, this difference is not well characterized. This study investigates whether patient satisfaction differences exist in providers who treat both pediatric and adult patients. Study Design: Retrospective review. Setting: Tertiary medical center. Methods: In this cross-sectional study, Press Ganey surveys (PGS) completed by patients or parents on their first-time visit with 5 general otolaryngology providers from July 2014 to March 2022 were analyzed. Surveys were categorized by child (<18 years old) or adult and consisted of 14 items including 6 service domains of access, visit, nursing, provider, personal issues, and assessment. Analysis was performed with Walsh's t test and analysis of variance. Multivariable logistic regression, controlling for wait times and provider, evaluated the likelihood of highest satisfaction scores (HI-SCORES) based on age. Results: A total of 2549 patients (135 pediatric, 2414 adults) completed the PGS on their initial visit. There was no significant difference in the mean overall satisfaction scores between pediatric and adult patients. Further analysis of service domains among pediatric patients found the mean score in the access domain to be higher for the 6- to 11-year-old age group (0-5 years old: 85.5 ± 20.5 [mean ± SD], 6-11 years old: 94.7 ± 11.5, 12-17 years old: 87.3 ± 15.4, P = .03). Pediatric patients did not have a significantly higher likelihood (odds ratio = 1.1, 95% confidence interval: 0.8-1.6, P > .05) of reporting HI-SCORES compared to adults after covariate adjustment. Conclusion: There was no significant difference in patient satisfaction scores for providers who treat pediatric and adult patients utilizing the same facility and scheduling team.

Excessive left anterior hippocampal and caudate activation in schizophrenia underlie cognitive underperformance in a virtual navigation task.

We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies.

Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma.

PURPOSE: Glioblastoma (GBM) patient outcomes remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: Here, we report the findings of four subjects enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells (PBMCs) pre- and post-NeoVax for subjects 1-3 using IFNg-ELISPOT assay. A statistically significant increase in IFNg producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from subject 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest NeoVax did stimulate expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in GBM patients.

Crystallographic Studies of KRAS in Complex with Small Molecules and RAS-Binding Proteins.

RAS proteins play a vital role in regulating downstream signaling and essential cellular processes, positioning them as key players in normal cellular physiology and disease development. Among the various isoforms of RAS, KRAS stands out as one of the most frequently mutated genes in human cancer. The prevalence of RAS mutations in cancer often involves single amino acid substitutions at codons 12, 13, or 61. These mutations disrupt the RAS protein's inherent ability to transition between its active and inactive states, resulting in a constant activation signal and driving uncontrolled cell growth. Crystallization and structural analysis of KRAS with inhibitors and RAS-binding proteins play a pivotal role in unraveling the structural and mechanistic details of KRAS function, aiding in drug discovery efforts, and advancing our understanding of KRAS-driven diseases. Here, we present our experimental methodology for crystallizing KRAS in the presence of covalent or non-covalent small molecules and proteins acting as effectors or regulators of RAS. We detail the techniques for successful crystallization and the subsequent optimization of crystallization conditions. The resulting crystals and their structures will provide valuable insights into the key interactions between KRAS and its partner proteins or potential inhibitors, offering a foundation for developing targeted therapies that are more potent and selective against KRAS-driven cancers.

Multicenter Registry of Adenomas of the Pituitary and Related Disorders: Initial Description of Cushing Disease Cohort, Surgical Outcomes, and Surgeon Characteristics.

BACKGROUND AND OBJECTIVES: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies. METHODS: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission. RESULTS: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years. CONCLUSION: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD.

Laser interstitial thermal therapy for new and recurrent meningioma: a prospective and retrospective case series.

OBJECTIVE: Meningiomas are the most common primary brain tumors in adults and a subset are aggressive lesions resistant to standard therapies. Laser interstitial thermal therapy (LITT) has been successfully applied to other brain tumors, and recent work aims to explore the safety and long-term outcome experiences of LITT for both new and recurrent meningiomas. The authors' objective was to report safety and outcomes data of the largest cohort of LITT-treated meningioma patients to date. METHODS: Eight United States-based hospitals enrolled patients with meningioma in the Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN) prospective multicenter registry and/or contributed additional retrospective enrollments for this cohort study. Demographic, procedural, safety, and outcomes data were collected and analyzed using standard statistical methods. RESULTS: Twenty adult patients (12 prospective and 8 retrospective) with LITT-targeted meningiomas were accrued. Patients underwent LITT for new (6 patients) and recurrent (14 patients) tumors (ranging from the 1st to 12th recurrence). The 30-day complication rate was 10%. Twenty percent of patients (4/20) had exhausted all other treatment options. Median length of follow-up was 1.3 years. One-third of new (2/6) and one-half of recurrent (7/14) meningiomas had disease progression during follow-up. One-year estimated local control (LC), progression-free survival, and overall survival rates were 55.3%, 48.4%, and 86.3%, respectively. In the 12 patients who had ≥ 91% ablative coverage, 1-year estimated LC was 61.4%. The complication rate was 10% (2/20), with 1 complication being transient and resolving postoperatively. CONCLUSIONS: This cohort study supports the safety of the procedure for this tumor type. LITT can offer a much-needed treatment option, especially for patients with multiply recurrent meningiomas who have limited remaining alternatives.

Immune checkpoint inhibitor-mediated polymyalgia rheumatica versus primary polymyalgia rheumatica: comparison of disease characteristics and treatment requirement.

OBJECTIVES: To compare clinical characteristics, imaging findings and treatment requirements of patients with immune checkpoint inhibitor-mediated polymyalgia rheumatica (ICI-PMR) and primary PMR. METHODS: This single centre, retrospective cohort study compared ICI-PMR in patients with cancer (n = 15) to patients with primary PMR (n = 37). A comparison was made between clinical symptoms, laboratory markers, ultrasonography,18F-FDG-PET/CT findings and treatment requirements related to PMR. RESULTS: Patients with ICI-PMR less frequently fulfilled the EULAR/ACR classification criteria for PMR (66.7%) than patients with primary PMR (97.3%). Morning stiffness, weight loss and elevation of the ESR were less frequently seen in patients with ICI-PMR. No differences were observed regarding the presence of inflammatory lesions on ultrasound of the shoulders and hips between the two groups. The Leuven and the Leuven/Groningen 18F-FDG-PET/CT scores were significantly lower in the ICI-PMR group. Finally, the ICI-PMR group could be managed with less glucocorticoids than the primary PMR group. CONCLUSION: Our findings indicate that ICI-PMR may have a milder course with less inflammation than primary PMR on 18F-FDG-PET/CT. ICI-mediated PMR patients can be managed with a relatively low glucocorticoid dose. Our study underscores that ICI-PMR should be regarded as PMR-like syndrome.

Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy.

Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating anti-tumor immune memory while minimizing multi-mechanistic immune suppression. A critical aspect of these therapies is the controlled, spatiotemporal delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME). Architectures such as spherical nucleic acids or poly(beta-amino ester)/dendrimer-based nanoparticles have shown promising results in preclinical models due to their multivalency and abilities to activate antigen-presenting cells and prime antigen-specific T cells. These nanostructures also permit systematic variation to optimize their distribution, TME accumulation, cellular uptake, and overall immunostimulatory effects. Delving deeper into the relationships between nanotherapeutic structures and their performance will accelerate nano-drug development and pave the way for the rapid clinical translation of advanced nanomedicines. In addition, the efficacy of nanotechnology-based immunotherapies may be enhanced when integrated with emerging precision surgical techniques, such as laser interstitial thermal therapy, and when combined with systemic immunotherapies, particularly inhibitors of immune-mediated checkpoints and immunosuppressive adenosine signaling. In this perspective, we highlight the potential of emerging treatment modalities, combining advances in biomedical engineering and neurotechnology development with existing immunotherapies to overcome treatment resistance and transform the management of GBM. We conclude with a call to action for researchers to leverage these technologies and accelerate their translation into the clinic.

Glioblastoma-infiltrating CD8+ T cells are predominantly a clonally expanded GZMK+ effector population.

Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) with paired V(D)J sequencing, respectively, on TIL from two cohorts of patients totaling 15 patients with high grade glioma, including GBM or astrocytoma, IDH mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared to matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T cell subset within the GBM microenvironment and which may harbor potential therapeutic implications.

Congenital Cytomegalovirus Testing Outcomes From the ValEAR Trial.

OBJECTIVE: To determine the positivity rate of congenital cytomegalovirus (cCMV) testing among universal, hearing-targeted CMV testing (HT-cCMV) and delayed targeted dried blood spot (DBS) testing newborn screening programs, and to examine the characteristics of successful HT-cCMV testing programs. STUDY DESIGN: Prospective survey of birth hospitals performing early CMV testing. SETTING: Multiple institutions. METHODS: Birth hospitals participating in the National Institutes of Health ValEAR clinical trial were surveyed to determine the rates of cCMV positivity associated with 3 different testing approaches: universal testing, HT-cCMV, and DBS testing. A mixed methods model was created to determine associations between successful HT-cCMV screening and specific screening protocols. RESULTS: Eighty-two birth hospitals were surveyed from February 2019 to December 2021. Seven thousand six hundred seventy infants underwent universal screening, 9017 infants HT-cCMV and 535 infants delayed DBS testing. The rates of cCMV positivity were 0.5%, 1.5%, and 7.3%, respectively. The positivity rate for universal CMV screening was less during the COVID-19 pandemic than that reported prior to the pandemic. There were no statistically significant drops in positivity for any approach during the pandemic. For HT-cCMV testing, unique order sets and rigorous posttesting protocols were associated with successful screening programs. CONCLUSION: Rates of cCMV positivity differed among the 3 approaches. The rates are comparable to cohort studies reported in the literature. Universal CMV prevalence decreased during the pandemic but not significantly. Institutions with specific order set for CMV testing where the primary care physician orders the test and the nurse facilitates the testing process exhibited higher rates of HT-cCMV testing.

A lesion in two: Buruli ulcer and squamous cell carcinoma coexistence.

The concurrent diagnoses of Buruli ulcer (BU) and cutaneous squamous cell carcinoma (SCC) is a phenomenon not previously described, despite the fact that both conditions are highly prevalent in Australia. This report presents an intriguing case of concurrent diagnoses, with clues alluding to more than one skin condition being present. The case involves a 73-year-old man with BU diagnosed on the scalp, an atypical location, which led to the consideration of malignancy, ultimately revealing concurrent SCC. This case highlights the importance of considering both conditions in patients with epidemiological risk factors, necessitating multiple lines of investigation for accurate diagnosis. Medical practitioners must remain vigilant and incorporate this possibility into their diagnostic algorithms for suspicious skin lesions to optimize treatment and outcomes. This is the first recorded instance of simultaneous diagnosis, underlining the need for enhanced awareness and attention to these unique cases.

EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no specific treatment for FXS due to the lack of therapeutic targets. We report here that Elongation Factor 1α (EF1α) forms a complex with two other proteins: Tripartite motif-containing protein 3 (TRIM3) and Murine double minute (Mdm2). Both EF1α-Mdm2 and EF1α-TRIM3 protein complexes are increased in the brain of Fmr1 knockout mice as a result of FMRP deficiency, which releases the normal translational suppression of EF1α mRNA and increases EF1α protein levels. Increased EF1α-Mdm2 complex decreases PSD-95 ubiquitination (Ub-PSD-95) and Ub-PSD-95-C1q interaction. The elevated level of TRIM3-EF1α complex is associated with decreased TRIM3-Complement Component 3 (C3) complex that inhibits the activation of C3. Both protein complexes thereby contribute to a reduction in microglia-mediated phagocytosis and dendritic spine pruning. Finally, we created a peptide that disrupts both protein complexes and restores dendritic spine plasticity and behavioural deficits in Fmr1 knockout mice. The EF1α-Mdm2 and EF1α-TRIM3 complexes could thus be new therapeutic targets for FXS.

Efficient and robust estimation of many-qubit Hamiltonians.

Characterizing the interactions and dynamics of quantum mechanical systems is an essential task in developing quantum technologies. We propose an efficient protocol based on the estimation of the time-derivatives of few qubit observables using polynomial interpolation for characterizing the underlying Hamiltonian dynamics and Markovian noise of a multi-qubit device. For finite range dynamics, our protocol exponentially relaxes the necessary time-resolution of the measurements and quadratically reduces the overall sample complexity compared to previous approaches. Furthermore, we show that our protocol can characterize the dynamics of systems with algebraically decaying interactions. The implementation of the protocol requires only the preparation of product states and single-qubit measurements. Furthermore, we improve a shadow tomography method for quantum channels that is of independent interest and discuss the robustness of the protocol to various errors. This protocol can be used to parallelize the learning of the Hamiltonian, rendering it applicable for the characterization of both current and future quantum devices.

Trunk postural control during unstable sitting among individuals with and without low back pain: A systematic review with an individual participant data meta-analysis.

INTRODUCTION: Sitting on an unstable surface is a common paradigm to investigate trunk postural control among individuals with low back pain (LBP), by minimizing the influence lower extremities on balance control. Outcomes of many small studies are inconsistent (e.g., some find differences between groups while others do not), potentially due to confounding factors such as age, sex, body mass index [BMI], or clinical presentations. We conducted a systematic review with an individual participant data (IPD) meta-analysis to investigate whether trunk postural control differs between those with and without LBP, and whether the difference between groups is impacted by vision and potential confounding factors. METHODS: We completed this review according to PRISMA-IPD guidelines. The literature was screened (up to 7th September 2023) from five electronic databases: MEDLINE, CINAHL, Embase, Scopus, and Web of Science Core Collection. Outcome measures were extracted that describe unstable seat movements, specifically centre of pressure or seat angle. Our main analyses included: 1) a two-stage IPD meta-analysis to assess the difference between groups and their interaction with age, sex, BMI, and vision on trunk postural control; 2) and a two-stage IPD meta-regression to determine the effects of LBP clinical features (pain intensity, disability, pain catastrophizing, and fear-avoidance beliefs) on trunk postural control. RESULTS: Forty studies (1,821 participants) were included for the descriptive analysis and 24 studies (1,050 participants) were included for the IPD analysis. IPD meta-analyses revealed three main findings: (a) trunk postural control was worse (higher root mean square displacement [RMSdispl], range, and long-term diffusion; lower mean power frequency) among individuals with than without LBP; (b) trunk postural control deteriorated more (higher RMSdispl, short- and long-term diffusion) among individuals with than without LBP when vision was removed; and (c) older age and higher BMI had greater adverse impacts on trunk postural control (higher short-term diffusion; longer time and distance coordinates of the critical point) among individuals with than without LBP. IPD meta-regressions indicated no associations between the limited LBP clinical features that could be considered and trunk postural control. CONCLUSION: Trunk postural control appears to be inferior among individuals with LBP, which was indicated by increased seat movements and some evidence of trunk stiffening. These findings are likely explained by delayed or less accurate corrective responses. SYSTEMATIC REVIEW REGISTRATION: This review has been registered in PROSPERO (registration number: CRD42021124658).

Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state.

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted.

Association of county-level socioeconomic status with meningioma incidence and outcomes.

BACKGROUND: Prior literature suggests that individual socioeconomic status (SES) may influence incidence, treatments, and survival of brain tumor cases. We aim to conduct the first national study to evaluate the association between US county-level SES and incidence, treatment, and survival in meningioma. METHODS: The Central Brain Tumor Registry of the United States analytic dataset, which combines data from CDC's National Program of Cancer Registries (NPCR) and National Cancer Institute's Surveillance, Epidemiology, and End Results Program, was used to identify meningioma cases from 2006 to 2019. SES quintiles were created using American Community Survey data. Logistic regression models were used to evaluate associations between SES and meningioma. Cox proportional hazard models were constructed to assess the effect of SES on survival using the NPCR analytic dataset. RESULTS: A total of 409 681 meningioma cases were identified. Meningioma incidence increased with higher county-level SES with Q5 (highest quintile) having a 12% higher incidence than Q1 (incidence rate ratios (IRR) = 1.12, 95%CI: 1.10-1.14; P < .0001). The Hispanic group was the only racial-ethnic group that had lower SES associated with increased meningioma incidence (Q5: age-adjusted incidence ratio (AAIR) = 9.02, 95%CI: 8.87-9.17 vs. Q1: AAIR = 9.33, 95%CI: 9.08-9.59; IRR = 0.97, 95%CI: 0.94-1.00; P = .0409). Increased likelihood of surgical treatment was associated with Asian or Pacific Islander non-Hispanic individuals (compared to White non-Hispanic (WNH)) (OR = 1.28, 95%CI: 1.23-1.33, P < .001) and males (OR = 1.31, 95%CI: 1.29-1.33, P < .001). Black non-Hispanic individuals (OR = 0.90, 95%CI: 0.88-0.92, P < .001) and those residing in metropolitan areas (OR = 0.96, 95%CI: 0.96-0.96, P < .001) were less likely to receive surgical treatment compared to WNH individuals. Overall median survival was 137 months, and survival was higher in higher SES counties (Q5 median survival = 142 months). CONCLUSIONS: Higher county-level SES was associated with increased meningioma incidence, surgical treatment, and overall survival. Racial-ethnic stratification identified potential disparities within the meningioma population. Further work is needed to understand the underpinnings of socioeconomic and racial disparities for meningioma patients.

Cyclooxygenase inhibition does not blunt thermal hyperemia in skeletal muscle of humans.

Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. The cyclooxygenase pathway is active in skeletal muscle, is heat sensitive, and contributes to cutaneous thermal hyperemia in young healthy humans. Therefore, the purpose of this study was to test the hypothesis that cyclooxygenase inhibition would attenuate blood flow in the vastus lateralis muscle during localized heating. Twelve participants (6 women) were studied on two separate occasions: 1) time control (i.e., no ibuprofen); and 2) ingestion of 800 mg ibuprofen, a nonselective cyclooxygenase inhibitor. Experiments were randomized, counter-balanced, and separated by at least 10 days. Pulsed short-wave diathermy was used to induce unilateral deep heating of the vastus lateralis for 90 min, whereas the contralateral leg served as a thermoneutral control. Microdialysis was utilized to bypass the cutaneous circulation and directly measure local blood flow in the vastus lateralis muscle of each leg via the ethanol washout technique. Heat exposure increased muscle temperature and local blood flow (both P < 0.01 vs. baseline). However, the thermal hyperemic response did not differ between control and ibuprofen conditions (P ≥ 0.2). Muscle temperature slightly decreased for the thermoneutral leg (P < 0.01 vs. baseline), yet local blood flow remained relatively unchanged across time for control and ibuprofen conditions (both P ≥ 0.7). Taken together, our data suggest that inhibition of cyclooxygenase-derived vasodilator prostanoids does not blunt thermal hyperemia in skeletal muscle of young healthy humans.NEW & NOTEWORTHY Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. Using a pharmacological approach combined with microdialysis, we found that thermal hyperemia in the vastus lateralis muscle was well maintained despite the successful inhibition of cyclooxygenase. Our results suggest that cyclooxygenase-derived vasodilator prostanoids do not contribute to thermal hyperemia in skeletal muscle of young healthy humans.

Indiana Pouch Continent Cutaneous Urinary Diversion After Robotic-assisted Radical Cystectomy: A 16-Year Experience.

BACKGROUND: Population-based practice patterns in the United States reveal continent diversions are only performed in 8%-10.4% of patients.1-4 Ideally, for patients undergoing radical cystectomy the choice of urinary diversion should be influenced by clinical factors and patient preference, with discussions surrounding quality of life. Unfortunately, receipt of continent diversion has been shown to be influenced by a plethora of other factors such as surgeon preference/training, geography, socioeconomic status, gender, and hospital volume.1-3 Thus, by providing detailed instruction and long-term follow-up, we hope to mitigate some of these disparities by changing the perceptions regarding feasibility and complications of continent diversions. OBJECTIVE: To provide step-by-step instruction and to report long-term clinical outcomes in bladder cancer patients receiving an Indiana pouch continent cutaneous urinary diversion (CCUD) after robot-assisted radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS: After Institutional Review Board approval, a prospectively maintained bladder cancer database was queried for patients with T1-T4, N0-N1, M0 bladder cancer undergoing radical cystectomy with CCUD at a tertiary referral center from 2004 to 2020. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complications at 30- and 90-day were recorded according to the Clavien-Dindo classification. Continence rates were recorded by chart review. RESULTS AND LIMITATIONS: A total of 97 patients were included with a median follow-up of 93months. Clinically, 91.8% had ≤T2 disease and 29.9% received neoadjuvant chemotherapy. The median length of surgery was 8.0 hours, length of hospital stay was 8.3days, and urinary continence rate was 99.0%. The overall complication rate was 73.2% and 76.5% at 30- and 90-day, respectively. The major complication rate (Clavien III-V) was 17.5% at 30-day and 22.7% at 90-day. The most common major complications were abdominal infection and uretero-colonic stricture. The readmission rate was 21.4% and median overall survival was 108months. CONCLUSION: CCUD provides exceptional functional outcomes with acceptable complication rates compared to other diversion types. CCUD is a reliable reconstructive option and with this step-by-step video as a reference, we hope it will be offered to more patients.

Can Ganciclovir and Quercetin-P188 Ameliorate Cytomegalovirus Induced Hearing Loss?

OBJECTIVE: Determine whether combination therapy with ganciclovir (GCV) and a Quercetin-P188 solution improves hearing outcomes in a murine cytomegalovirus (CMV) model. METHODS: BALB/c mice were infected with murine CMV on postnatal day 3 (p3). Quercetin was solubilized in saline using P188 (QP188). Treatment groups received either GCV, QP188, GCV and QP188, or P188 delivery vehicle BID at 12-hour intervals via intraperitoneal injection. All treatment groups were treated for 14 days starting at p3. Uninfected controls were treated with the combined regimen, saline or P188 delivery vehicle. Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing at 4, 6, and 8 weeks of age. Temporal bones from separate CMV-infected groups were harvested at p10, and viral load was determined by quantitative polymerase chain reaction. RESULTS: CMV-infected mice receiving combination therapy GCV+QP188 demonstrated statistically significant lower ABR (p < 0.001) and DPOAE thresholds (p < 0.001) compared with mice treated with GCV monotherapy, QP188 monotherapy, and P188 delivery vehicle at 4, 6, and 8 weeks of age. GCV+QP188 combination therapy, GCV monotherapy, and QP188 monotherapy resulted in a nonsignificant reduction in mean viral titers compared to P188 monotherapy (p = 0.08). CONCLUSION: Combining GCV with the excipients quercetin and P188 effectively ameliorated CMV-induced sensorineural hearing loss in a murine model. This result may be partially explained by a reduction in viral titers in mouse temporal bones that correlate with in vitro studies demonstrating additive antiviral effect in cell culture. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1457-1463, 2024.