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Background: The management of acute hemorrhage in patients with previously treated head and neck squamous cell carcinoma (HNSCC) is challenging due to the lack of substantial evidence to guide clinical decision making., Methods: A systematic review and retrospective chart review were performed to identify patients with a history of HNSCC who underwent either primary or adjuvant radiation therapy (RT) and presented with hemorrhagic complications requiring embolization. Patient characteristics, history, presentation, and outcomes were reviewed., Results: The systematic review included a total of 182 patients. Heterogeneity existed in outcomes reporting; 1-year overall survival approached 50%. From the retrospective chart review, 51 patients were included. Median survival time following hemorrhage was 2.2 months (range 1.2-11.4 months). Patients with malignancy at time of hemorrhage were identified as having worse survival., Conclusions: Acute hemorrhage in patients with a history of previously radiated HNSCC portends a high risk of mortality, with patients with active malignancy representing a worse prognostic group., (© 2024 Wiley Periodicals LLC.)

Background: Head and neck reconstruction after resection of cutaneous malignancies spans the entire reconstructive ladder. Local flaps, such as the bilobed flap, offer excellent versatility, negligible morbidity, and minimal hospitalization. However, there is sparse data regarding the bilobed flap for large defects of the head and neck., Methods: A retrospective case series identified patients undergoing head and neck reconstruction with a large bilobed flap for defect sizes ≥ 5 x 5 cm. Data collected included demographics, risk factors for impaired healing, operative variables, and complications., Results: Nineteen patients were included; 15 (79%) were male, and median age was 80 years (47-88). Twelve patients had pertinent comorbidities and risk factors, including diabetes mellitus, current smoker, prior radiation to the operative area, and immunosuppressive state. Ten (53%) patients experienced complications, including infection, necrosis, or hematoma. Eleven (58%) patients received adjuvant radiation. Eleven (58%) patients were discharged within 1 day., Conclusion: The large bilobed flap is an effective reconstructive technique for large head and neck cutaneous defects in properly selected patients. This flap can be a useful alternative to free tissue transfer in elderly patients., (© 2024 Wiley Periodicals LLC.)

Background: Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal blood vessel formation. One treatment for HHT-related arteriovenous malformations (AVMs) is sclerotherapy, which collapses the blood vessels by irritating the endothelial lining., Methods: This case series describes two HHT patients undergoing in-office sodium tetradecyl sulfate sclerotherapy for non-nasal telangiectasias and AVMs. The first patient had AVMs on the red lip while the second patient had an AVM and several telangiectasias on the tongue., Results: Both patients' AVMs required only one treatment visit and were no longer noticeable within a week. Neither of the patients had any side effects from treatment., Conclusion: Sclerotherapy was used to successfully treat HHT-related AVMs in-office with no scarring and is an option that should be considered by providers., Competing Interests: Declaration of competing interest Dr. Piccirillo reported a patent for various patient-reported outcomes with royalties paid from Washington University in St Louis; royalty payments from Washington University in St Louis for the licensing of the Sino-Nasal Outcome Test, Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia instrument, and Symptoms of Nocturnal Obstruction and Related Events instrument; serving on the external advisory boards of the Georgia Clinical & Translational Science Alliance and Frontiers Clinical and Translational Science Institute; and honorarium for serving as chair of the Data and Safety Study Monitoring Board for the Endotypic Traits and Obstructive Sleep Apnea Surgery study and for serving as a scientific consultant and co-chair of the study advisory committee of the Nasal Steroids, Irrigation, Oral Antibiotics and Subgroup Targeting for Effective Management of Sinusitis study. Dr. Peterson reported payments from Washington University in St Louis for the licensing of the Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE HHT) instrument., (Copyright © 2024. Published by Elsevier Inc.)

In this work, a heat transfer model is developed for thermally-driven material extrusion additive manufacturing of semicrystalline polymers that considers the heat generated during crystallization by coupling crystallization kinetics with heat transfer. The materials used in this work are Technomelt PA 6910, a semicrystalline hot melt adhesive with sub-ambient glass transition temperature (T g ) and slow crystallization, and PA 6/66, a traditional semicrystalline polyamide with a higher T g and fast crystallization. The coupled model shows that the released heat during crystallization depends on material selection, with Technomelt PA 6910 and PA 6/66's temperatures increased by less than 1 °C and up to 6.3 °C, respectively, due to enthalpy of crystallization. Increasing the layer time decreases the layer temperature as well as the initial crystallinity. However, its effect on final crystallinity in Technomelt PA 6910 is negligible due to continued crystallization of the material after printing. Experimental validation shows good agreement for Technomelt PA 6910, but consistently underpredicts PA 6/66 crystallinity. Increasing modeled environmental temperature leads to better agreement with experimental results for PA 6/66, suggesting that higher temperatures may have been experienced. Shear-induced crystallization may also be contributing to crystallinity in this material. The results from this model highlight the importance of and interrelationships between material and processing parameter selection and can aid in achieving quality prints from semicrystalline thermoplastics., (© 2024. The Author(s).)

Digital light processing (DLP) is rapidly growing in popularity as an additive manufacturing method for the fabrication of composite structures, and is an effective way to prepare high-resolution filled parts, such as ceramic green parts or composite magnets. Yet, higher solid loadings of resins and the resulting dramatic increases in viscosity limit DLP printing for applications that depend upon maximization of filler content. In this work, we investigate the capacity of a bimodal particle size distribution to enable the printing of a photosensitive resin containing up to 70 vol% of fillers. Formulations with unimodal and bimodal solid loadings ranging from 50 to 72 vol% are prepared and their viscoelastic properties measured through rotational rheometry. The zero-shear viscosity of these formulations is fit with a Krieger-Dougherty model, and the dense random close packing fraction of particles determined from the fit is found to be 76.3 vol%. Parts with fine positive and negative features are printed to evaluate the resolution achievable with highly filled photosensitive resins. The part printed with a 70 vol% formulation shows negative features as small as 860 μm, and positive feature as small as 380 μm. Finally, parts with complex patterns are prepared with previously tested formulations, and thermogravimetric analysis results show that the filler content within the parts remains relatively constant over a 3-h print, with a decrease of 2 vol% of solids for the final printed layers., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Streptococcus mutans is commonly associated with dental caries and the ability to form biofilms is essential for its pathogenicity. We recently identified the Pgf glycosylation machinery of S. mutans, responsible for the post-translational modification of the surface-associated adhesins Cnm and WapA. Since the four-gene pgf operon (pgfS-pgfM1-pgfE-pgfM2) is part of the S. mutans core genome, we hypothesized that the scope of the Pgf system goes beyond Cnm and WapA glycosylation. In silico analyses and tunicamycin sensitivity assays suggested a functional overlap between the Pgf machinery and the rhamnose-glucose polysaccharide synthesis pathway. Phenotypic characterization of pgf mutants (ΔpgfS, ΔpgfE, ΔpgfM1, ΔpgfM2, and Δpgf) revealed that the Pgf system is important for biofilm formation, surface charge, membrane stability, and survival in human saliva. Moreover, deletion of the entire pgf operon (Δpgf strain) resulted in significantly impaired colonization in a rat oral colonization model. Using Cnm as a model, we showed that Cnm is heavily modified with N-acetyl hexosamines but it becomes heavily phosphorylated with the inactivation of the PgfS glycosyltransferase, suggesting a crosstalk between these two post-translational modification mechanisms. Our results revealed that the Pgf machinery contributes to multiple aspects of S. mutans pathobiology that may go beyond Cnm and WapA glycosylation., (© 2023 John Wiley & Sons Ltd.)

Objectives: The lack of universal guidance on outcome measures for evaluating medication adherence enhancing interventions (MAEIs) poses a challenge for assessing their effectiveness. This literature review aimed to provide a systematic overview of outcome measures currently used for the value assessment of MAEIs., Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched MEDLINE, PsycINFO, Scopus, CINAHL, and Academic Search Complete for randomized and nonrandomized clinical trials, prospective cohort studies, model-based economic evaluations, and value frameworks published in English between January 2010 and September 2020. Two independent reviewers screened all titles and abstracts, followed by a full-text review. Due to the large number of relevant studies, data extraction was limited to articles published between January 2018 and September 2020. We collected data on the general characteristics of the study, the type of intervention, and the outcomes measured., Results: We screened 14 685 records and identified 308 articles for data extraction. Behavioral interventions were the most common (n = 143), followed by educational interventions (n = 110) and mixed-method interventions (n = 73). Outcomes were clustered into 7 categories with medication adherence (n = 286) being the most frequently measured, followed by clinical outcomes (n = 155), health-related quality of life (n = 57), resource use (n = 43), patient satisfaction (n = 31), economic outcomes (n = 18), and other outcomes (n = 76)., Conclusions: Various outcomes measures have been used to evaluate MAEIs, with only a small number of studies exploring economic and patient-reported outcomes. Future research is warranted to develop a consensus-based set of criteria for assessing MAEIs to facilitate the comparison of interventions and enable informed decision making., Competing Interests: Author Disclosures Links to the individual disclosure forms provided by the authors are available here., (Copyright © 2023 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Healthcare providers often hesitate to discuss medical cannabis (MC) due to limited understanding, risks and benefits, and misinformation. This reluctance is notable with older adult patients, despite MC's potential benefits. This study investigates whether primary care providers (PCPs) routinely inquire about MC when treating older adults and the frequency of such inquiries., Methods: A 23-question survey was emailed to 575 physicians, pharmacists, nurse practitioners, and physician assistants who completed a Pennsylvania Department of Health-approved MC course. The survey was conducted in 2022 to 2023, and the participants were drawn from a pool of individuals who completed the course between 2018 and 2022. PCPs need to be practicing in the Tri-state area and caring for older adults. Results were cross-tabulated to examine the relationship between healthcare practitioners' inquiries about MC and patients' questions about MC. McNemar and Chi-square tests were used for analysis., Results: Survey results revealed that PCPs were more likely to inquire about alcohol and tobacco use than cannabis with older adults ( P  < .0001). Patients were more likely to initiate conversations about MC use ( P  = .037). PCPs did not frequently inquire about cannabis use amongst their patients or consider it as a therapeutic option., Conclusion: This study underscores the prevalent reluctance among PCPs to initiate discussions about MC treatment with older adults. Further investigation is needed to identify how to improve communication regarding the risks and benefits of MC., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Elbready received summer salary support, Dr. Warner-Maron works for the sponsoring agency, Alden Geriatric Consultants, Inc., and Dr. Peterson is on a Medical Advisory board for a New Jersey Cannabis dispensary, Holistic LLC I.

Objective: The objective of this study was to explore the safety and feasibility of stellate ganglion blocks (SGBs) to treat persistent COVID-19-induced olfactory dysfunction (OD). Secondarily, the goal was to determine effect sizes to plan a future randomized clinical trial., Study Design: Prospective case series., Setting: Quaternary Care Academic Medical Center., Methods: In this single-arm pilot trial, adult participants with a COVID-19 diagnosis ≥ 12 months prior to enrollment with OD underwent bilateral SGBs. Subjects were followed for 1 month after completion of SGB. The primary outcome measure was the change in the Clinical Global Impression-Improvement Scale for smell loss. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT) and Olfactory Dysfunction Outcomes Rating (ODOR)., Results: Twenty participants were enrolled with a mean (SD) age of 46 (11) years and a mean (SD) duration of OD of 21 (5) months. At 1 month, 10 (50%) participants experienced at least slight subjective improvement in their OD, 11 (55%) attained a clinically meaningful improvement in smell identification using the UPSIT, and 7 (35%) achieved a clinically meaningful improvement in olfactory-specific quality of life (QoL) measured by the ODOR. The median difference between UPSIT scores at baseline and 1 month was 6 (95% confidence interval: 3-11), exceeding the minimal clinically important difference of 4. There were no serious adverse events., Conclusion: Sequential SGBs for COVID-19-associated OD were safe and associated with modest improvements in subjective olfaction, odor identification, and olfactory-specific QoL. A placebo-controlled trial is warranted to determine the efficacy of SGBs for COVID-19-associated OD., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Kunal Srivastava,1 Anamika Arora,1 Aditi Kataria,1 Joseph C Cappelleri,2 Alesia Sadosky,3 Andrew M Peterson41HERON Health PVT, Chandigarh, India; 2Pfizer Inc, Statistics, Groton, CT, USA; 3Pfizer Global Health Economics and Outcomes Research, New York, NY, USA; 4Mayes College of Healthcare Business and Policy, University of the Sciences, Philadelphia, PA, USAObjectives: To assess the impact of reduced frequency of oral therapies from multiple-dosing schedules to a once-daily (OD) dosing schedule on adherence, compliance, persistence, and associated economic impact.Methods: A meta-analysis was performed based on relevant articles identified from a comprehensive literature review using MEDLINE® and Embase®. The review included studies assessing adherence with OD, twice-daily (BID), thrice-daily (TID), and four-times daily (QID) dosing schedules and costs associated with optimal/suboptimal adherence among patients with acute and chronic diseases. Effect estimates across studies were pooled and analyzed using the DerSimonian and Laird random-effect model.Results: Forty-three studies met inclusion criteria, and meta-analyzable data were available from 13 studies. The overall results indicated that OD schedules were associated with higher adherence rates (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.80–5.23; P < 0.001 for OD versus > OD dosing) and compliance rates (OR 3.50, 95% CI 1.73–7.08; P < 0.001 for OD versus > OD dosing); persistence rates showed the same direction but were not statistically significant (OR 1.43, 95% CI 0.62–3.29; P = 0.405 for OD versus BID dosing). Results for each of the conditions were consistent with those observed overall with respect to showing the benefits of less frequent dosing. From a health economic perspective, higher adherence rates with OD relative to multiple dosing in a number of conditions were consistently associated with corresponding lower costs of health care resources utilization.Conclusion: Current meta-analyses suggested that across acute and chronic disease states, reducing dosage frequency from multiple dosing to OD dosing may improve adherence to therapies among patients. Improving adherence may result in subsequent decreases in health care costs.Keywords: compliance, dosage frequency, persistence, random-effect meta-analyses

Comments on the early lectures of 1588 given by scientist Galileo Galilei on Dante's Inferno and their relation to Galileo's mature theory of the laws of scaling presented in his book 'Two New Sciences,' given by Mark Peterson. Explanation regarding Galileo's reticence on questions of scale; Reference of the center of the earth as the center of the universe in Galileo's 1588 lectures.

Machine learning techniques were used to predict tensile properties of material extrusion-based additively manufactured parts made with Technomelt PA 6910, a hot melt adhesive. An adaptive data generation technique, specifically an active learning process based on the Gaussian process regression algorithm, was employed to enable prediction with limited training data. After three rounds of data collection, machine learning models based on linear regression, ridge regression, Gaussian process regression, and K-nearest neighbors were tasked with predicting properties for the test dataset, which consisted of parts fabricated with five processing parameters chosen using a random number generator. Overall, linear regression and ridge regression successfully predicted output parameters, with < 10% error for 56% of predictions. K-nearest neighbors performed worse than linear regression and ridge regression, with < 10% error for 32% of predictions and 10-20% error for 60% of predictions. While Gaussian process regression performed with the lowest accuracy (< 10% error for 32% of prediction cases and 10-20% error for 40% of predictions), it benefited most from the adaptive data generation technique. This work demonstrates that machine learning models using adaptive data generation techniques can efficiently predict properties of additively manufactured structures with limited training data., (© 2023. The Author(s).)

Importance: Patient-reported outcome measures (PROMs) allow clinicians and researchers to assess health-related information from a patient's perspective. These measures have been used more frequently over the last several decades, but an associated minimal clinically important difference (MCID) is needed to optimize their utility. This narrative review identified the top 100 most-cited otolaryngology-related PROM development and validation publications and assessed the presence and characteristics of the PROMs' associated MCID., Observations: In this narrative review, a literature search in Scopus and Web of Science was conducted on June 29, 2022, using keywords related to PROM development and validation studies in otolaryngology and reference lists. Studies that met the definition of a PROM and assessed an otolaryngologic disorder or study population were included for full-text review. After full-text review of 188 articles, the top 100 most-cited PROM development and validation publications, resulting in 106 total PROMs, were chosen for review. A total of 39 (37%) of the identified PROMs had an associated MCID. Of those reporting an MCID, 14 (35.9%) used an anchor-based method, 12 (30.8%) used a distribution-based method, 10 (25.6%) used both, and 3 (7.7%) did not specify or used neither method. Rhinology had the greatest number of PROMs with an associated MCID (16 of 24, 66%), and pediatrics had the fewest (1 of 13, 7.7%). The median number of citations of PROMs with an MCID was higher than those without an MCID., Conclusions and Relevance: The majority of the most-cited PROMs in otolaryngology lack an associated MCID. These data indicated that there are a multitude of PROMs that have been cited hundreds of times and used for decades without the ability to identify whether a particular change in score on the instrument is clinically meaningful. There is a need to determine and validate MCIDs for commonly used PROMs to aid clinical research and trial interpretation.

Objective: With the rise of medical and recreational cannabis use among older adults, concerns about the potential risks and benefits of cannabis use are increasing. This pilot study aimed to determine the attitudes, beliefs, and perceptions of older adults toward cannabis as a medicinal product, to establish a foundation for future research on how healthcare providers communicate with this population regarding cannabis., Methods: A cross-sectional survey was conducted on adults aged 65 and older living in Philadelphia. The survey included questions related to participants' demographics, knowledge, attitudes, beliefs, and perceptions of cannabis. Participants were recruited via flyer distributions, publications in newsletters, and a local newspaper. Surveys were conducted from December 2019 through May 2020. Quantitative data were presented using counts, mean, median, and percentages, and qualitative data were analyzed by categorizing common responses., Results: The study aimed to recruit 50 participants, of whom 47 met the requirements, and had their data analyzed, resulting in an average age of 71 years. The majority of participants were male (53%) and Black (64%). Seventy-six percent of participants considered cannabis a highly important treatment for older adults, and 42% considered themselves highly knowledgeable about cannabis. Over half of the participants reported being asked about tobacco (55%) or alcohol (57%) use by their PCP compared to 23% being asked about cannabis. Participants indicated that they most commonly turned to the internet and social media for information about cannabis, while only a small number mentioned relying on their primary care physician (PCP) for such information., Discussion: The results of this pilot study highlight the need for accurate and reliable information about cannabis for older adults and their healthcare providers. As the use of cannabis as a therapy continues to rise, it is crucial for healthcare providers to address misconceptions and encourage older adults to seek out evidence-based research. Further research is needed to explore healthcare providers' perceptions of cannabis therapy and how they can better educate older adults.

Importance: Olfactory dysfunction (OD) is an increasingly common and morbid condition, especially given the ongoing COVID-19 pandemic. Thus, the ability to reproducibly measure smell loss-associated quality of life (QOL) and its response to treatment is paramount., Objective: To develop and validate a concise and visually appealing smell loss-associated QOL patient-reported outcome measure for OD., Design, Setting, and Participants: A secondary analysis of comments to an online survey by 1000 patients with olfactory dysfunction published in 2013 was used as the primary source to generate items of the Olfactory Dysfunction Outcomes Rating (ODOR). In addition, 30 patients with OD enrolled in 2 clinical studies at a tertiary care medical center (Washington University) were asked to identify their main concerns associated with smell loss. And finally, 4 otolaryngologists reviewed the items generated from the online survey and the patients' interviews to identify any additional items. Prospective study design was used for data collection from the 30 patients and 4 otolaryngologists. Prospective study design was used for survey validation. Validation of the ODOR was performed with 283 patients enrolled in several prospective studies at a single institution that completed the ODOR as an outcome measure., Main Outcomes and Measures: Item generation and selection were the outcomes of ODOR development. The psychometric and clinimetric measures evaluated for validation were internal consistency, test-retest reliability, face and content validity, concurrent validity, and discriminant validity. Minimal clinically important difference was also determined., Results: The ODOR is a 28-item instrument with each item scored as either no difficulty or very rarely bothered (0) to complete difficulty or very frequently bothered (4) with a total instrument score range of 0 to 112 points. Higher scores indicate higher degree of dysfunction and limitation. Validation in the cohort of 283 patients (mean [SD] age, 47.0 [14.4] years; 198 female participants [73%]; 179 White participants [80%]) revealed that the instrument has high internal consistency (Cronbach α = 0.968), test-retest reliability (r = 0.90 [95% CI, 0.81-0.95]), face validity, content validity, concurrent validity (r = 0.87 [95% CI, 0.80-0.91] compared with the Questionnaire of Olfactory Disorders-Negative Statements; ρ = -0.76 [95% CI, -0.81 to -0.71] compared with a patient-reported symptom severity scale), and divergent validity (mean score difference, -33.9 [95% CI, -38.3 to -29.6] between normosmic patients and hyposmic/anosmic patients). The minimal clinically important difference was 15 points. The estimated time for survey completion was approximately 5 minutes., Conclusions and Relevance: In this survey creation and validation study, the ODOR was shown to be a novel, concise, reliable, and valid patient-reported outcome measure of OD-associated QOL. It can be used to measure physical problems, functional limitations, and emotional consequences associated with OD and how they change after a given intervention, which is clinically applicable and particularly pertinent given the growing burden of OD associated with COVID-19.

Objective: The current literature on unilateral coronal craniosynostosis is replete with repair techniques and surgical outcomes; however, information regarding neurodevelopment remains unclear. Therefore, the aim of this systematic review and meta-analysis was to comprehensively assess the neurodevelopmental outcomes of patients with unicoronal craniosynostosis compared with their healthy peers or normative data., Methods: A systematic review of the Ovid MEDLINE, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases from database inception to January 19, 2022, was performed. Included studies assessed neurodevelopment of patients with unicoronal craniosynostosis. Two independent reviewers selected studies and extracted data based on a priori inclusion and exclusion criteria. Results of developmental tests were compared with normative data or controls to generate Hedges' g statistics for meta-analysis. The quality of included studies was evaluated using the National Institutes of Health Assessment Tool., Results: A total of 19 studies were included and analyzed, with an overall fair reporting quality. A meta-analysis of 325 postoperative patients demonstrated that scores of general neurodevelopment were below average but within one standard deviation of the norm (Hedges' g = -0.68 [95% CI -0.90 to -0.45], p < 0.001). Similarly, postoperative patients exhibited lower scores in verbal, psychomotor, and mathematic outcome assessments., Conclusions: This systematic review and meta-analysis found that patients with unicoronal craniosynostosis had poorer neurodevelopment, although scores generally remained within the normal range. These data may guide implementation of regular neurocognitive assessments and early learning support of patients with unicoronal craniosynostosis.

Objective: Limited knowledge exists regarding the information patients seek online about sinus procedures. The goals of our study were to identify the most searched online queries regarding functional endoscopic sinus surgery (FESS) and balloon sinuplasty and evaluate the sources to which patients are directed., Study Design: Observational., Setting: Online Google Database., Methods: Google data were analyzed using the search engine optimization tool Ahrefs. People Also Ask (PAA) questions (extracted from Google searches) helped identify questions for analysis of search query volume. Search results were categorized into specific topics, and the source (eg, academic vs medical practice) of the information was identified. The JAMA benchmark criteria were used to determine the quality of the online resource., Results: The most searched term (average monthly queries) on Google was "sinus surgery" (13,190), followed by "balloon sinuplasty" (9212). For FESS and balloon sinuplasty, most questions focused on treatment of sinusitis (71.64% vs 79.19%) and preoperative inquiries about sinus issues (11.50% vs 11.35%). Answers to PAA questions for FESS were obtained from academic sources at a higher frequency compared to balloon sinuplasty (26.7% vs 10.3%, P = .016) but a lower frequency from medical practice websites (15.2% vs 29.3%, P = .042). The mean (SD) JAMA scores for FESS and balloon sinuplasty sources were 1.59 (1.46) and 1.40 (1.46), respectively., Conclusion: There is a high volume of online search queries regarding FESS and balloon sinuplasty. The quality of the sources could be improved by addressing authorship, attribution, disclosure, and currency. This information may help otolaryngologists better address patient queries.

Objectives: (1) Identify anatomic contributions to chronic rhinosinusitis (CRS) necessitating revision endoscopic sinus surgery (RESS). (2) Create a clinical acronym to guide imaging review prior to RESS that addresses pertinent sites of disease and potential sites of surgical morbidity., Data Sources: Ovid MEDLINE, Embase and Medline via Embase.com, Web of Science Core Collection, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar., Review Methods: Systematic search was performed using a combination of standardized terms and keywords. Studies were included if they investigated anatomic contributions to persistent CRS requiring RESS or the relationship between anatomic landmarks and surgical morbidity. Identified studies were screened by title/abstract, followed by full-text review. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were strictly followed., Results: In total, 599 articles met screening criteria, 89 were eligible for full-text review, and 27 studies were included in the final review. The identified anatomic sites of interests are broad; the most frequently cited anatomic region was retained anterior ethmoid cells (22/27 studies), followed by posterior ethmoid cells (14/27 studies). Using the consolidated information, a clinical acronym, REVISIONS, was created: Residual uncinate, Ethmoid cells (agger, Haller, supraorbital), Vessels (anterior and posterior ethmoid), Infundibulum, Septal deviation, I (eye) compartment, Onodi cell, Natural os, and Skull base slope and integrity., Conclusions: The REVISIONS acronym was developed as a tool to distill the unique anatomic contributions of primary endoscopic sinus surgery failure into a format that can be easily incorporated in preoperative radiologic review and surgical planning to optimize outcomes and minimize complications.

Mechanical properties of additively manufactured structures fabricated using material extrusion additive manufacturing are predicted through combining thermal modeling with entanglement theory and molecular dynamics approaches. A one-dimensional model of heat transfer in a single road width wall is created and validated against both thermography and mechanical testing results. Various model modifications are investigated to determine which heat transfer considerations are important to predicting properties. This approach was able to predict tear energies on reasonable scales with minimal information about the polymer. Such an approach is likely to be applicable to a wide range of amorphous and low crystallinity thermoplastics., (© 2022. The Author(s).)

Zinc is a trace metal that is essential to all forms of life, but that becomes toxic at high concentrations. Because it has both antimicrobial and anti-inflammatory properties and low toxicity to mammalian cells, zinc has been used as a therapeutic agent for centuries to treat a variety of infectious and non-infectious conditions. While the usefulness of zinc-based therapies in caries prevention is controversial, zinc is incorporated into toothpaste and mouthwash formulations to prevent gingivitis and halitosis. Despite this widespread use of zinc in oral healthcare, the mechanisms that allow Streptococcus mutans, a keystone pathogen in dental caries and prevalent etiological agent of infective endocarditis, to overcome zinc toxicity are largely unknown. Here, we discovered that S. mutans is inherently more tolerant to high zinc stress than all other species of streptococci tested, including commensal streptococci associated with oral health. Using a transcriptome approach, we uncovered several potential strategies utilized by S. mutans to overcome zinc toxicity. Among them, we identified a previously uncharacterized P-type ATPase transporter and cognate transcriptional regulator, which we named ZccE and ZccR respectively, as responsible for the remarkable high zinc tolerance of S. mutans. In addition to zinc, we found that ZccE, which was found to be unique to S. mutans strains, mediates tolerance to at least three additional metal ions, namely cadmium, cobalt, and copper. Loss of the ability to maintain zinc homeostasis when exposed to high zinc stress severely disturbed zinc:manganese ratios, leading to heightened peroxide sensitivity that was alleviated by manganese supplementation. Finally, we showed that the ability of the ΔzccE strain to stably colonize the rat tooth surface after topical zinc treatment was significantly impaired, providing proof of concept that ZccE and ZccR are suitable targets for the development of antimicrobial therapies specifically tailored to kill S. mutans., Competing Interests: The authors have declared that no competing interests exist.

Background: Medication-related problems in older Blacks with diabetes mellitus (DM) are not well established. Objectives: To describe the frequency of medication-related problems in older Blacks with DM presenting to the emergency department (ED). Methods: The study was a cross-sectional analysis of baseline data from a randomized controlled trial evaluating Blacks aged ≥60 years of age presenting to the ED. Polypharmacy, potentially inappropriate medication (PIM) use, and anticholinergic score were evaluated. Results: Of 168 patients (median age = 68, range 60-92), most ( n = 164, 98%) were taking ≥5 medications, and 67 (39.9%) were taking a PIM. A majority ( n = 124, 74%) were taking a medication with an anticholinergic score ≥1. Number of medications was correlated with number of PIMs ( r = .22, p = .004) and anticholinergic score ( r = .50, p < .001). Conclusion: Polypharmacy and PIM use was common in older Blacks with DM.

Objective: To evaluate the efficacy and safety of intranasal theophylline saline irrigation on olfactory recovery in patients with post-viral olfactory dysfunction (PVOD)., Methods: Between May 2019 and April 2020, we conducted a double-blinded, placebo-controlled randomized clinical trial of adults with 6-36 months of PVOD. Patients were randomized to nasal theophylline saline irrigation or placebo saline irrigation twice a day for 6 weeks. The primary outcome was the Global Rating of Smell Change. Secondary outcomes were changes in the University of Pennsylvania Smell Identification Test (UPSIT) and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS)., Results: Twenty-two patients (n = 12, theophylline; n = 10, placebo) completed the study. Slightly more patients in the theophylline group (33%) reported improved smell compared to the placebo group (30%, difference 3.3%, 95% CI -35.6% to 42.3%). The median differences in pre- and post-treatment UPSIT and QOD-NS change between the two groups were 1 (95% CI -3 to 5) and -10 (95% CI -15 to -4), respectively in favor of theophylline. Three patients receiving theophylline and 2 receiving placebo had clinically meaningful improvements on the UPSIT (difference 5%, 95% CI -30% to 40%). There were no adverse events, and serum theophylline levels were undetectable in 10/10 patients., Conclusions: While safe, there were no clinically meaningful differences in olfactory change between the two groups except for olfaction-related quality of life, which was better with theophylline. The imprecise estimates suggest future trials will need substantially larger sample sizes or treatment modifications, such as increasing the theophylline dose, to observe larger treatment effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To measure growth-related changes in orbital volume from childhood to the late teenage years using cone-beam computed tomography (CBCT) scans., Methods: This retrospective cohort study involved 65 (24 male, 41 female) healthy Caucasian children (ages 6-18 years) with existing serial craniofacial CBCT scans. CBCT scans were available for 292 orbits. Each orbit was transformed into a closed space with well-defined boundaries, and orbital volume was measured using manual segmentation. A novel statistical analysis was applied to extract the maximum amount of longitudinal information from the data. Intra- and inter-operator correlation coefficients were calculated from replications performed on a random subset of 10% of the sample., Results: Orbital volume increased at a rate of 1-2% annually until the late teenage years. Intra- and inter-operator agreement between repeated measurements were >90%., Conclusions: Orbital volume increases by 1-2% per year throughout childhood continuing until the late teenage years. This annual increase is large enough to be clinically relevant as it may lead to less-than-optimal long term surgical outcomes when reconstructive surgery for the pediatric anophthalmic socket is required., (© 2022. The Author(s).)

Objectives/hypothesis: Neurogenic cough affects 11% of Americans and causes significant detriment to quality of life. With the advent of novel therapies, the objective of this review is to determine how procedural therapies (e.g., superior laryngeal nerve block) compare to other established pharmacologic and non-pharmacologic treatments for neurogenic cough., Methods: With the assistance of a medical librarian, a systematic review was performed using PICOS (patients, interventions, comparator, outcome, study design) format: adults with neurogenic cough receiving any pharmacologic or non-pharmacologic treatment for neurogenic cough compared to adults with neurogenic cough receiving any other relevant interventions, or treated as single cohorts, assessed with cough-specific quality of life outcomes, in all study designs and case series with ≥ 10 cases. Case reports, review articles, non-human studies, non-English language articles, and unavailable full-text articles were excluded., Results: There were 2408 patients with neurogenic cough in this review, treated with medical therapy (77%), speech therapy (19%), both medical and speech therapy (1%), and procedural therapy (3%). The included studies ranged from low to intermediate quality. Overall, most interventions demonstrated successful improvement in cough. However, the heterogeneity of included study designs precluded direct comparisons between intervention types., Conclusion: This meta-analysis compared various treatments for neurogenic cough. Procedural therapy should be considered in the armamentarium of neurogenic cough treatments, particularly in patients refractory to, or intolerant of, the side effects of medical therapy. Lastly, this review illuminates key areas for improving neurogenic cough diagnosis, such as strict adherence to diagnostic and treatment guidelines, sophisticated reflux testing, and standardized, consistent outcome reporting. Laryngoscope, 132:107-123, 2022., (© 2020 American Laryngological, Rhinological and Otological Society Inc, “The Triological Society” and American Laryngological Association (ALA).)

Interfacial adhesion dictates properties and performance of both composites and adhesively bonded structures. Weak adhesion at the interfaces of polymer composites leads to void formation and debonding, which adversely affect composite structural integrity and mechanical performance. This work investigated the relationship between surface wettability and interfacial fracture energy with the goal of tailoring interfacial adhesion within polymer composites. A series of model functionalized surfaces was created using silane coupling agents with different organo-functionalities to alter surface wettability. Based on the analysis of interfacial fracture energy between a thermosetting elastomeric polymer network and model surfaces, interfacial adhesion was found to be positively correlated to resin wettability. The results provide a fast and simple approach to screen different material combinations for the development of novel polymeric composites and adhesively bonded structures with tailorable adhesion., Competing Interests: There are no conflicts of to declare., (This journal is © The Royal Society of Chemistry.)

Spatial transcriptomics techniques such as STARmap [15] enable the subcellular detection of RNA transcripts within complex tissue sections. The data from these techniques are impacted by optical microscopy limitations, such as shading or vignetting effects from uneven illumination during image capture. Downstream analysis of these sparse spatially resolved transcripts is dependent upon the correction of these artefacts. This paper introduces a novel non-parametric vignetting correction tool for spatial transcriptomic images, which estimates the illumination field and background using an efficient iterative sliced histogram normalization routine. We show that our method outperforms the state-of-the-art shading correction techniques both in terms of illumination and background field estimation and requires fewer input images to perform the estimation adequately. We further demonstrate an important downstream application of our technique, showing that spatial transcriptomic volumes corrected by our method yield a higher and more uniform gene expression spot-calling in the rodent hippocampus. Python code and a demo file to reproduce our results are provided in the supplementary material and at this github page: https://github.com/BoveyRao/Non-parametric-vc-for-sparse-st.

Introduction: Current evidence suggests that cannabinoids are safe with minimal side effects and are effective in managing chronic pain. Data also show that medical marijuana (MM) may improve quality of life (QoL) among patients. However, there are little data showing the health-related QoL (HRQoL) benefit in MM patients using it for pain. The purpose of this study was to determine if there is a relationship between HRQol and MM use in patients using it to relieve pain., Methods: All pain patients aged 18 years or older enrolled in the Pennsylvania MM program were eligible for inclusion. Recruited subjects completed 4 surveys - at enrollment (baseline) then 2, 4, and 8 weeks post-enrollment. We used the EQ-5D survey tool for measuring HRQoL. The primary outcome measure was the change in the EQ-5D Index Score from survey 2 to survey 4 (6 week difference). Secondary outcomes included self-reported pain and health scores. Data were analyzed using a paired t test and repeated-measures multivariable analysis to control for both gender and length of time between surveys., Results: 1,762 people responded to the screening request, and 1,393 (79%) met screening criteria. Of those, 353 (25.3%) agreed to participate and 51% completed all 4 surveys, for a final sample of 181 with 85 male and 95 female and one nonbinary subject. The average age was 41.21 (SD = 12.9) years, with no difference between genders. The adjusted HRQoL score improved from 0.722 to 0.747 ( p = 0.011) from survey 2 to survey 4, as did the self-reported pain and health scores. The EQ-5D subscales revealed no change in mobility or usual activities, significant improvement in anxiety and pain, and a significant worsening in self-care., Conclusion: The results show a significant improvement in HRQoL among patients using MM for pain. The EQ-5D subscales validated the pain improvement and also showed an improvement in anxiety. However, the decline in the self-care subscale may have tempered the overall improvement in HRQoL, and further research into which aspects of self-care are impacted by MM use in this population is warranted. Overall, there is a positive relationship between MM use and HRQoL in patients using it for pain., Competing Interests: Dr. Andrew Peterson is on the Medical Advisory Board for Holistic Industries, a cannabis dispensary company seeking licensure in the state of New Jersey. He also serves as the executive director of the Substance Use Disorders Institute at University of the Sciences, which offers a 4-h Pennsylvania Department of Health-approved MM education program. Christine Le has no conflicts to declare. Tyler Dautrich has no conflicts to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Electronic-cigarette's (ECIGs) popularity has grown over the last decade and changed the way individuals administer nicotine. Preclinical research is imperative for understanding the addictive properties and health-risks associated with ECIG use; however, there is not a standard dosing regimen used across research laboratories. The main objective was to determine how vapor puff durations, administration session length, and flavored e-liquid alter general and mood-disorder related behaviors while providing a foundation of vapor administration parameters. Adult male and female C57BL/6 mice were exposed to several nicotine-free unflavored vapor puff durations (1, 3, 6, or 10 s) and vapor administration session lengths (10 and 30 min) then measured on the following assays: locomotor activity (LMA), tail suspension test (TST), and light-dark test. The effects of mecamylamine and the time-course of vapor-induced depression of LMA also were assessed. Additionally, mice were exposed to flavored (strawberry and adventurers tobacco blend) vapor inhalation and measured on locomotor activity, tail suspension test, and light-dark test. Following both 10 and 30 min vapor administration session, there was a puff duration-dependent decrease in distance traveled, time in center, and rearing. The vapor-induced depression of LMA was not mediated by nicotine or nicotinic acetylcholine receptor (nAChR) activation and lasted 60-90 min. The 10 s puff duration produced an anxiogenic-like effect in the light-dark test by decreasing the time spent in the light side. Vapor inhalation did not significantly alter TST behavior. No significant effects of sex or flavor were found. The anxiogenic-like effects of nicotine-free vapor inhalation are concerning as many adolescents vape nicotine-free flavored e-liquid, and there is an association between ECIGs and mood disorders. Additionally, these studies demonstrate that vapor puff duration, but not vapor administration session length, is an important variable to consider during research design as it can become a confounding variable and alter baseline behaviors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Trace metals are essential to all domains of life but toxic when found at high concentrations. Although the importance of iron in host-pathogen interactions is firmly established, contemporary studies indicate that other trace metals, including manganese and zinc, are also critical to the infectious process. In this study, we sought to identify and characterize the zinc uptake system(s) of Streptococcus mutans, a keystone pathogen in dental caries and a causative agent of bacterial endocarditis. Different than other pathogenic bacteria, including several streptococci, that encode multiple zinc import systems, bioinformatic analysis indicated that the S. mutans core genome encodes a single, highly conserved, zinc importer commonly known as AdcABC. Inactivation of the genes coding for the metal-binding AdcA (ΔadcA) or both AdcC ATPase and AdcB permease (ΔadcCB) severely impaired the ability of S. mutans to grow under zinc-depleted conditions. Intracellular metal quantifications revealed that both mutants accumulated less zinc when grown in the presence of a subinhibitory concentration of a zinc-specific chelator. Notably, the ΔadcCB strain displayed a severe colonization defect in a rat oral infection model. Both Δadc strains were hypersensitive to high concentrations of manganese, showed reduced peroxide tolerance, and formed less biofilm in sucrose-containing media when cultivated in the presence of the lowest amount of zinc that support their growth, but not when zinc was supplied in excess. Collectively, this study identifies AdcABC as the major high affinity zinc importer of S. mutans and provides preliminary evidence that zinc is a growth-limiting factor within the dental biofilm., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Growth factor-eluting polymer systems have been widely reported to improve cell and tissue outcomes; however, measurements of actual growth factor concentration in cell culture conditions are limited. The problem is compounded by a lack of knowledge of growth factor half-lives, which impedes efforts to determine real-time growth factor concentrations. In this work, the half-life of basic fibroblast growth factor (FGF2) was determined using enzyme linked immunosorbent assay (ELISA). FGF2 release from polyelectrolyte multilayers (PEMs) was measured and the data was fit to a simple degradation model, allowing for the determination of FGF2 concentrations between 2 and 4 days of culture time. After the first hour, the FGF2 concentration for PEMs assembled at pH = 4 ranged from 2.67 ng/mL to 5.76 ng/mL, while for PEMs assembled at pH = 5, the concentration ranged from 0.62 ng/mL to 2.12 ng/mL. CRL-2352 fibroblasts were cultured on PEMs assembled at pH = 4 and pH = 5. After 2 days, the FGF2-eluting PEM conditions showed improved cell count and spreading. After 4 days, only the pH = 4 assembly condition had higher cells counts, while the PEM assembled at pH = 5 and PEM with no FGF2 showed increased spreading. Overall, the half-life model and cell culture study provide optimal concentration ranges for fibroblast proliferation and a framework for understanding how temporal FGF2 concentration may affect other cell types.

Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer's disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

Proper labeling of seafood is important to prevent economic deception and protect public health. The goal of this research was to investigate prepackaged frozen fish for Country of Origin Labeling (COOL) compliance, species labeling, net weights/short weighting, and percent glaze. A total of 111 frozen prepackaged fish fillets were purchased from grocery stores in Southern California (USA). Samples were designated as COOL compliant if they displayed both procurement method and country of origin in accordance with COOL requirements. Species labeling was examined by comparing the species identified with DNA barcoding to the acceptable market names provided in the FDA Seafood List . Net weights and percent glaze were determined by recording the weight of each product before and after deglazing. Of the 111 samples, only 1 was noncompliant with COOL and 10 samples (9%) were short-weighted. The average percent glaze was 5%, with seven samples having >10% glaze. Most fish (95.5%) were correctly labeled with regards to species. Species substitution was discovered in two samples and three samples had unacceptable market names. The results of this study indicate high COOL compliance and minimal species mislabeling in prepackaged frozen fish fillets. However, there is a need for increased focus on short weighting and/or overglazing of frozen fish products., Competing Interests: The authors declare no conflict of interest., (© 2021 Published by Elsevier Ltd.)

Importance: Overall, the prognosis of sinonasal squamous cell carcinoma (SCC) is poor. This malignancy can arise de novo or from inverted papillomas, but it is unclear whether survival differences between the 2 pathologies exist., Objective: To assess for survival differences between patients with sinonasal de novo SCC (dnSCC) and those with inverted papilloma-associated SCC (IPSCC)., Data Sources: A search of Ovid MEDLINE, Embase, Scopus, and the Cochrane Library from inception to January 23, 2020, with cross-referencing of retrieved studies, was performed. Additional data were requested from authors., Study Selection: Inclusion and exclusion criteria were designed to capture studies with survival outcomes of adults with sinonasal SCC who underwent regular treatment. Clinical trials, cohort studies, case-control studies, and case series with more than 10 adults aged 18 years or older with sinonasal SCC were included. Exclusion criteria were studies on non-SCC sinonasal neoplasms, studies without histopathologic diagnoses, non-English language articles, nonhuman animal studies, and abstract-only articles. Two blinded investigators (J.J.L., A.M.P., T.W.E., or N.S.W.) screened each abstract and full text, and a third investigator (J.J.L. or P.P.) adjudicated discrepancies. Of 729 unique citations, 26 studies of 1194 total patients were included., Data Extraction and Synthesis: Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. The Methodological Index for Nonrandomized Studies (MINORS) criteria were used to assess study quality. Two blinded investigators (J.J.L., A.M.P., T.W.E., or N.S.W.) independently extracted data from each study. Data were pooled using a random-effects model., Main Outcomes and Measures: The primary outcome was overall survival, and secondary outcomes were disease-free and disease-specific survival. Before data collection, it was hypothesized that the dnSCC cohort would have worse survival outcomes than the IPSCC cohort., Results: One study of patients with dnSCC, 12 studies of patients with IPSCC, and 5 studies with both cohorts were included in the meta-analysis of overall survival. The pooled 5-year overall survival rate for 255 patients with dnSCC was 56% (95% CI, 41%-71%; I2 = 83.8%) and for 475 patients with IPSCC was 65% (95% CI, 56%-73%; I2 = 75.7%). Five comparative studies of both cohorts totaling 240 patients with dnSCC and 155 patients with IPSCC were included in another meta-analysis. The pooled overall survival hazard ratio was 1.87 (95% CI, 1.24-2.84; I2 = 0%)., Conclusions and Relevance: This systematic review and meta-analysis found that patients with dnSCC had almost a 2-fold increased risk of mortality compared with those with IPSCC. Large, multicenter studies are necessary to validate these findings before considering treatment alterations such as de-escalation based on histopathology.

Introduction: Our objective was to study the impact and clinical operation of an integrated model for free specialized dermatology care via collaboration between an academic institution and a nonprofit outpatient clinic through an analysis of patient demographics and care provided., Methods: Hope@UMHS is a partnership between the University of Michigan Health System (UMHS) and Hope Clinic (HC) which provides free specialty consultations to uninsured residents of Southeast Michigan. A retrospective chart review was completed for patients referred to the UMHS Dermatology clinic as part of the HOPE@UMHS collaboration from April 2012 through February 2020., Results: Of the 294 referred patients, 264 were managed in 30 clinic sessions over 8 years, staffed by 92 unique volunteers. Patients most commonly presented with atopic dermatitis (10.5%), seborrheic dermatitis (7.9%), and actinic keratosis (7.4%). The majority of patients (68.2%) were prescribed at least one new medication. Nine skin cancers, including one melanoma, were diagnosed and treated. There were 102 procedures performed. Eighty-seven percent of patients received conclusive evaluation and treatment at the time of their consultation., Conclusion: Our experience illustrates that providing free, comprehensive dermatology care in a university hospital by partnering with a nonprofit clinic is both feasible and beneficial to the greater community.

Lasers with ultrashort pulse durations have become ubiquitous in various applications, including ocular surgery. Therefore, we need to consider the role of nonlinear optical effects, such as supercontinuum generation during propagation within the ocular media, when evaluating their potential hazard. We used a NIR femtosecond laser to generate a supercontinuum within an artificial eye. We recorded the visible spectra of the supercontinuum generated and calculated the energy contained within the visible band. Our results indicate that for wavelengths between 1350 nm and 1450 nm the energy contained within the visible band of the generated white light supercontinuum may surpass current safety exposure limits, and pose a risk of injury to the retina., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Importance: Other than nasal moisturizers, no standard-of-care medical therapy exists for epistaxis in hereditary hemorrhagic telangiectasia (HHT). With epistaxis as the greatest cause of morbidity in patients with HHT, there is a need to identify effective topical therapies., Objective: To determine the efficacy and safety of an intranasal timolol thermosensitive gel vs placebo thermosensitive gel in treating HHT-associated epistaxis., Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial was conducted from October 29, 2019, to May 20, 2020, at a tertiary care center. A total of 27 patients with HHT and moderate-to-severe epistaxis were recruited and included in this prespecified analysis: 14 in the timolol group and 13 in the placebo group. Inclusion criteria included (1) age 18 years or older, (2) clinical or genetic diagnosis of HHT, (3) screening Epistaxis Severity Score (ESS) of 4 or greater and 2 or more nosebleeds cumulatively lasting at least 5 minutes per week, (4) stable epistaxis pattern over the preceding 3 months, and (5) no change in epistaxis treatment or nasal hygiene regimen in the preceding month. Exclusion criteria included (1) contraindications to systemic β-blocker administration, (2) use of medications interacting with timolol, (3) use of antiangiogenic medications in the last month before recruitment, and (4) use of anticoagulants, antiplatelets, or fibrinolytic therapies within the last month., Interventions: Novel thermosensitive intranasal timolol (0.1%) gel vs placebo thermosensitive gel applied twice daily to each nostril for 8 weeks., Main Outcomes and Measures: The primary outcome was the median change in ESS and percentage of participants reaching the minimal clinically important difference in ESS. Secondary outcomes were changes in Clinical Global Impression-Severity and Clinical Global Impression-Improvement scores, Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia, and hemoglobin level., Results: Of 27 participants randomized (median [range] age, 55 [20-76] years; 14 women [52%]; 25 White [93%]), a total of 23 patients with HHT completed the primary outcome measure. Within the timolol gel and placebo gel groups, respectively, the median change (range) in ESS was 2.32 (0.22 to 5.97) vs 1.96 (-0.91 to 5.98), and 9 of 11 (82%) vs 9 of 12 (75%) participants experienced a clinically meaningful improvement in ESS. Twenty-two of the 23 participants (96%) reported improvement via the Clinical Global Impression-Improvement score, with 81% vs 58% of participants reporting reduced severity of epistaxis in the timolol vs placebo group, respectively. Of participants completing the Nasal Outcome Score for Epistaxis in HHT at follow-up visit, 7 of 10 (70%) in the timolol group achieved a clinically important difference vs 5 of 10 (50%) in the placebo group. There was no change in hemoglobin level between or within groups. Zero participants in the placebo group and 2 of 13 (15%) in the timolol group withdrew because of adverse events., Conclusions and Relevance: Thermosensitive gel, alone or in combination with timolol, was highly effective in reducing HHT-associated epistaxis. The timolol group had greater improvement in epistaxis and quality of life than the placebo group, but effect estimates were imprecise, and no definitive conclusions on the superiority of timolol can be drawn. Physicians treating patients with HHT-associated epistaxis should consider a thermosensitive gel (with or without timolol) for their patients., Trial Registration: ClinicalTrials.gov Identifier: NCT04139018.

Importance: Epistaxis is the greatest cause of morbidity in patients with hereditary hemorrhagic telangiectasia (HHT); because of this, a validated epistaxis-specific quality-of-life instrument for HHT should be made available., Objective: To develop and validate an epistaxis-specific quality-of-life patient-reported outcome measure for HHT., Design, Setting, and Participants: This survey study focused on the development and validation of the Nasal Outcome Score for Epistaxis (NOSE) in HTT (NOSE HHT) outcome measure with data prospectively collected from December 10, 2019, to March 15, 2020. A total of 401 patients were recruited from within the Cure Hemorrhagic Telangiectasia online patient advocacy social media network, the Washington University HHT Center of Excellence, and a randomized clinical trial investigating an intranasal timolol gel for HHT-associated epistaxis., Main Outcomes and Measures: Face and content validity, factor analysis, internal consistency as measured through Cronbach α, construct validity, responsiveness to change, and minimal clinically important difference., Results: The NOSE HHT was developed and validated with a possible score ranging discretely from 0 to 4 for each of the 29 items and a total score ranging continuously from 0 to 4 after dividing by the total number of items answered. A total of 401 participants completed the NOSE HHT. Factor analysis identified 3 factors that matched the a priori specified subgroups of particular aspects of life affected by HHT-associated epistaxis: physical problems (mean [SD] magnitude, 1.59 [0.83]), functional limitations (mean [SD] magnitude, 1.28 [0.84]), and emotional consequences (mean [SD] magnitude, 1.95 [1.02]). The instrument had high internal consistency with an overall Cronbach α of 0.960. Convergent validity determined the total NOSE HHT score to be a strong predictor of disease severity; total NOSE HHT score can be split up into the following epistaxis severity categories: mild (0-1), moderate (1.01-2), and severe (>2). The instrument was found to be sensitive to change, and the minimal clinically important difference for the total NOSE HHT score was 0.46., Conclusions and Relevance: Evaluation of the consistency, reliability, and responsiveness of the NOSE HHT survey found it to be a valid instrument to assess severity and change in epistaxis. Study results suggest that the NOSE HHT survey is clinically applicable and useful as an outcome measure of future HHT-associated epistaxis trials.

The glutamatergic system has emerged as a novel pathway for treating major depressive disorder (MDD) with the focus on producing both rapid and sustained antidepressant effects. Dextromethorphan is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has produced antidepressant-like effects in forced swim and tail suspension tests (TST); however, the rapid and sustained antidepressant-like effects of dextromethorphan have not been evaluated. This study evaluated the rapid and sustained (24 h) antidepressant-like effects of dextromethorphan (0-32 mg/kg) in C56BL/6 mice using the novelty-induced hypophagia (NIH) test and TST, respectively. Additionally, we evaluated anxiety-related behavior and locomotor effects of dextromethorphan (0-56.0 mg/kg) using the light-dark and open field tests. Dextromethorphan (32 mg/kg) produced acute (30 min) antidepressant-like effects in TST, but failed to produce antidepressant-like effects 24 h after drug administration. Treatment of dextromethorphan (32 mg/kg) alone or in combination with CYP2D6 enzyme inhibitor Quinidine (32 mg/kg) failed to produce rapid antidepressant-like effects by increasing the latency to drink in the NIH test rather than decreasing the latency to drink. Dextromethorphan (56 mg/kg) produced an anxiogenic-like effect by decreasing the time spent in the light side, number of entries, and latency to enter the light side in the light-dark test. Administration of dextromethorphan (0-56 mg/kg) did not significantly alter locomotor activity. Although dextromethorphan is considered a noncompetitive NMDA receptor antagonist, dextromethorphan binds to several monoaminergic receptors (SERT and NET) and likely produces the antidepressant-like effects through these receptors similar to traditional antidepressant drugs. Additionally, these results suggest that the therapeutic window for dextromethorphan in the clinical population is small as similar doses produce antidepressant-like and anxiogenic-like behaviors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acid-sensing ion channel (ASIC) subunits 1a and 3 are highly expressed in central and peripheral sensory neurons, respectively. Endogenous biomolecule zinc plays a critical role in physiological and pathophysiological conditions. Here, we found that currents recorded from heterologously expressed ASIC1a/3 channels using the whole-cell patch-clamp technique were regulated by zinc with dual effects. Co-application of zinc dose-dependently potentiated both peak amplitude and the sustained component of heteromeric ASIC1a/3 currents; pretreatment with zinc between 3 to 100 µM exerted the same potentiation as co-application. However, pretreatment with zinc induced a significant inhibition of heteromeric ASIC1a/3 channels when zinc concentrations were over 250 µM. The potentiation of heteromeric ASIC1a/3 channels by zinc was pH dependent, as zinc shifted the pH dependence of ASIC1a/3 currents from a pH 50 of 6.54 to 6.77; whereas the inhibition of ASIC1a/3 currents by zinc was also pH dependent. Furthermore, we systematically mutated histidine residues in the extracellular domain of ASIC1a or ASIC3 and found that histidine residues 72 and 73 in both ASIC1a and ASIC3, and histidine residue 83 in the ASIC3 were responsible for bidirectional effects on heteromeric ASIC1a/3 channels by zinc. These findings suggest that histidine residues in the extracellular domain of heteromeric ASIC1a/3 channels are critical for zinc-mediated effects.

Background: Medication adherence is crucial for the successful treatment among elderly patients with diabetes taking oral antidiabetic medications (OAMs). Cost of medications, lack of insurance coverage, and low income are major contributing factors towards medication nonadherence. State pharmaceutical assistance programs (SPAPs) provide medications at little or no cost to income-eligible patients and have potential to improve medication adherence among elderly patients. Despite this, limited research has focused on the association of medication adherence with health care utilization among elderly patients enrolled in SPAPs, and inclusion of health care costs as an outcome is even rarer., Objective: To evaluate the relationship between adherence to OAMs and hospital utilization and costs among elderly patients with diabetes who were enrolled in a SPAP., Methods: This retrospective observational study included elderly patients with diabetes enrolled in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly (PACE) program in 2015. Medication adherence was estimated as the proportion of days covered (PDC; adherent: PDC≥80%, nonadherent: PDC < 80%). Hospital utilization and costs were estimated using hospital discharge records from the Pennsylvania Health Care Cost Containment Council. Multiple adjusted regression analyses were used to examine the association of medication adherence with hospital utilization (all-cause and diabetes-related number of inpatient hospital visits and length of stay [LOS]) and costs., Results: Among 9,497 elderly PACE enrollees with diabetes, 81% were adherent, and 21% were hospitalized. Compared with adherent patients, patients who were nonadherent to OAMs had twice the odds of all-cause and diabetes-related hospitalization. Controlling for covariates, nonadherent patients had 27% more all-cause (95% CI = 9%-36%) and 21% more diabetes-related (95% CI = 5%-40%) hospital visits than adherent patients. Covariate-adjusted LOS for nonadherent patients was 24% longer than that of adherent patients for all-cause hospitalization (95% CI = 1.171-1.311) and 12.7% longer for diabetes-related hospitalization (95% CI = 1.036-1.227). Medication nonadherence was associated with significantly greater all-cause ($22,670 vs. $16,383; P < 0.0001) and diabetes-related ($13,518 vs. $12,634; P = 0.0003) hospitalization costs., Conclusions: Among SPAP-enrolled elderly patients, nonadherence to OAMs was significantly associated with increased risk of hospitalization, longer hospital stays, and greater hospitalization costs. Attention is needed to improve medication adherence among elderly receiving financial assistance to pay their prescriptions to reduce economic burden on the health care system., Disclosures: No outside funding supported this study. The authors have nothing to disclose.