Characterization of Glucokinases from Pathogenic Free-Living Amoebae.

Infection with pathogenic free-living amoebae, including Naegleria fowleri, Acanthamoeba spp., and Balamuthia mandrillaris, can lead to life-threatening illnesses, primarily because of catastrophic central nervous system involvement. Efficacious treatment options for these infections are lacking, and the mortality rate due to infection is high. Previously, we evaluated the N. fowleri glucokinase (NfGlck) as a potential target for therapeutic intervention, as glucose metabolism is critical for in vitro viability. Here, we extended these studies to the glucokinases from two other pathogenic free-living amoebae, including Acanthamoeba castellanii (AcGlck) and B. mandrillaris (BmGlck). While these enzymes are similar (49.3% identical at the amino acid level), they have distinct kinetic properties that distinguish them from each other. For ATP, AcGlck and BmGlck have apparent Km values of 472.5 and 41.0 µM, while Homo sapiens Glck (HsGlck) has a value of 310 µM. Both parasite enzymes also have a higher apparent affinity for glucose than the human counterpart, with apparent Km values of 45.9 µM (AcGlck) and 124 µM (BmGlck) compared to ~8 mM for HsGlck. Additionally, AcGlck and BmGlck differ from each other and other Glcks in their sensitivity to small molecule inhibitors, suggesting that inhibitors with pan-amoebic activity could be challenging to generate.

Vascular events in patients with head and neck cancer: A systematic review and meta-analysis.

OBJECTIVE: To assess the incidence of vascular events in patients with head and neck cancer. REVIEW METHODS: Primary studies identified through April 2023. Meta-analysis was performed. RESULTS: There were 146 studies included in the systematic review. Rates of events were collected in the overall group, those with chemoprophylaxis, and those that underwent surgery, radiation, or chemotherapy. Of 1 184 160 patients, 4.3% had a vascular event. Radiation therapy had highest risk of overall events and stroke when compared to surgery and chemotherapy. Chemotherapy had a higher risk of stroke and overall events when compared to surgery. CONCLUSIONS: Vascular events occur in 4%-5% of patients with head and neck cancer. Our data does not support the use of routine anticoagulation. Patients undergoing radiation therapy had the highest frequency of events.

Adult Laryngomalacia: A Scoping Review.

OBJECTIVE: This review sought to determine the characteristics of adults diagnosed with new onset laryngomalacia including airway symptoms, laryngoscopic findings, treatments, and outcomes. Moreover, we wanted to highlight suspected limitations in the literature. DATA SOURCES: Studies were identified through CINAHL, Cochrane Review, PubMed, and Scopus published between 1966 and 2023. REVIEW METHODS: The search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews checklist by 2 independent investigators. A meta-analysis of proportions and continuous measures was conducted. RESULTS: Of the 1121 abstracts identified, 33 articles pertaining to laryngomalacia in the adult population were included. The most common presenting symptoms were stridor at rest (78.3%, 65.1-88.3) and dyspnea with exertion (83.8%, 64.8-96.3). The most suspected etiology was exercise-induced (86.0%, 69.4-95.5), and the most common description of laryngomalacia on visualization was collapse of supraglottic structures during exercise (93.3%, 79.0-99.1). Nonsurgical options were attempted in 87.0% (54.0-99.1), which included oral appliances, respiratory retraining, breathing techniques, and working with a speech pathologist. Surgical options were ultimately performed in 84.2% (75.0-91.0). Complete resolution of symptoms following therapy was seen in 61.9% (48.0-74.6). CONCLUSION: Adult onset laryngomalacia is difficult to characterize. It typically presents in patients during exercise, with neurological injury, or idiopathically. Surgical management can lead to improvement or complete resolution of symptoms. The need for a universal nomenclature is highlighted in this review, as it is inconsistently classified.

Characteristics and outcomes of interventions for pediatric laryngomalacia: A systematic review with meta-analysis.

OBJECTIVES: To analyze characteristics of children treated for laryngomalacia to determine predictive factors and provide an updated meta-analysis on outcomes. METHODS: A systematic review was conducted according to PRISMA guidelines from inception to May 2, 2023, using CINAHL, PubMed, and Scopus databases. Study screening, data extraction, quality rating, and risk of bias assessment were performed by 2 independent reviewers. Data were meta-analyzed using fixed-/random-effects model to derive continuous measures (mean), proportions (%), and mean difference (Δ) with 95% confidence interval (CI). RESULTS: 100 articles were identified with information on outcomes of pediatric patients with laryngomalacia (N = 18,317). The mean age was 10.6 months (range: 0 to 252, 95%CI: 9.6 to 11.6, p = 0.00) with a 1.4:1 male to female ratio. Many patients presented with stridor (87.9%, 95% CI: 69.8 to 98.4), and the most common comorbidity at time of diagnosis was gastroesophageal reflux disease (48.8%, 95%CI: 40.9 to 56.8). Based on the patient population included in our analysis, 86.1% received supraglottoplasty (95% CI: 78.7 to 92.1). A total of 73.6% (95% CI: 65.5 to 81.0) had reported complete resolution of symptoms. For patients with a concurrent diagnosis of sleep disordered breathing receiving supraglottoplasty, the apnea-hypopnea index improved with a mean difference of -10.0 (95%CI: 15.6 to -4.5) events per hour post-treatment. CONCLUSIONS: Laryngomalacia continues to be a common problem in the pediatric population. Supraglottoplasty remains an effective treatment option leading to symptomatic improvement in many cases. For those with concurrent sleep disordered breathing, supraglottoplasty lowers the apnea-hypopnea index.

The placebo effect of sham rhinologic procedures in randomized controlled trials: A systematic review and meta-analysis.

KEY POINTS: Sham procedures produce a clinically significant impact on patient-reported outcome measures This effect should be considered when designing and interpreting the results of RCTs.

The placebo effect in randomized-controlled trials of medical treatments for chronic rhinosinusitis: A systematic review and meta-analysis.

BACKGROUND: The placebo effect observed in clinical trials evaluating medical treatments for chronic rhinosinusitis (CRS) is not well understood. This systematic review and meta-analysis sought to characterize the placebo effect present within CRS outcomes. METHODS: A systematic review of PubMed, Scopus, and Cumulated Index in Nursing and Allied Health Nursing (CINAHL) was performed. Randomized controlled trials (RCTs) evaluating medical treatments for CRS versus placebo were included. We assessed patient-reported (sino-nasal outcome test 22 [SNOT-22], nasal obstruction, sense of smell, nasal obstruction visual analogue score [VAS], sense of smell VAS, anterior rhinorrhea, and postnasal drip) and objective (Lund-Mackay Computed tomography (CT) score, peak nasal inspiratory flow [PNIF], nasal polyp scores, 40-item Smell Identification Test, serum IgE, and blood eosinophil levels) outcomes. RESULTS: Twenty-one RCTs were included, comprising 1437 patients (mean age 49.2 years). Biologics were the most common treatment investigated (n = 9). Eleven studies administered background steroids along with placebo. Following placebo administration, multiple patient-reported outcomes significantly decreased, including SNOT-22 (mean difference -9.49, 95% confidence interval [CI] [-11.26, -7.73]), nasal obstruction (-0.33 [-0.54, -0.13]), sense of smell (-0.22 [-0.33, -0.11]), nasal obstruction VAS (-2.47 [-2.87, -2.06]), and loss of smell VAS (-2.31 [-4.14, -0.47]) scores. For objective measures, significant changes occurred in Lund-Mackay CT score (-0.82, [-1.48, -0.16]) and PNIF (4.70, [4.76, 24.64]) with placebo. Placebo arms had the greatest impact when no background medications were used. CONCLUSIONS: Placebo treatments have a statistically and potentially clinically significant effect on patient-reported and some objective CRS outcomes. Further investigation is required to fully understand placebo effect, which could improve assessment of RCTs and impact patient care.

Effects of Body Positioning on Laryngeal Penetration and Aspiration in Children with Unilateral Vocal Cord Paralysis.

Objective: To evaluate laryngeal penetration and aspiration in upright and side-lying positions in children with unilateral vocal cord paralysis (VCP) who underwent modified barium swallow study (MBSS). Methods: A retrospective chart review (Pro00089051) of pediatric patients who were diagnosed with unilateral VCP and underwent MBSS was performed. Patients were identified using diagnostic code for VCP and based on diagnosis via flexible laryngoscopy. Once identified, MBSS notes were reviewed for data regarding laryngeal penetration, tracheal aspiration, and body position during the exam. Information was collected on the various consistencies of liquids used. The order of positioning was recorded in patients who had undergone both positions during the study. Data was analyzed using chi-square analysis. Results: 811 patients had undergone MBSS between 2011 and 2014. Of these, 90 patients were isolated with unilateral VCP, and of those 90 patients, 23 (26%) had undergone MBSS in both side-lying and upright positions. When all 90 patients were evaluated, there was no difference in penetration or aspiration noted in the side-lying or upright position with thin liquids. Importantly, among the 23 (26%) patients that had been studied in both positions, there were no significant differences in penetration or aspiration relating to body position with any consistency. Conclusion: Rates of penetration and aspiration were not associated with body position in patients who had undergone MBSS at our institution. However, due to an incomplete data set and a small sample size of those who underwent MBSS in both positions, these results should be further explored in prospective studies.

Editorial: Special Issue on the Epidemiology of Human Papilloma Virus-Associated Oropharyngeal Squamous Cell Carcinoma.

In this Special Issue of Cancers, the role of oncogenic human papilloma virus (HPV) with oropharyngeal squamous cell carcinoma is explored […].

Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases.

Pathogenic free-living amoebae (pFLA) can cause life-threatening central nervous system (CNS) infections and warrant the investigation of new chemical agents to combat the rise of infection from these pathogens. Naegleria fowleri glucokinase (NfGlck), a key metabolic enzyme involved in generating glucose-6-phosphate, was previously identified as a potential target due to its limited sequence similarity with human Glck (HsGlck). Herein, we used our previously demonstrated multifragment kinetic target-guided synthesis (KTGS) screening strategy to identify inhibitors against pFLA glucokinases. Unlike the majority of previous KTGS reports, our current study implements a "shotgun" approach, where fragments were not biased by predetermined binding potentials. The study resulted in the identification of 12 inhibitors against 3 pFLA glucokinase enzymes─NfGlck, Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck). This work demonstrates the utility of KTGS to identify small-molecule binders for biological targets where resolved X-ray crystal structures are not readily accessible.

Dual-Stage Picolinic Acid-Derived Inhibitors of Toxoplasma gondii.

Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both T. gondii parasite forms. Picolinic acid 23, designed from an antiparasitic benzamidobenzoic acid class with challenging ADME properties, showed 60-fold-enhanced solubility, a moderate LogD7.4, and a 30% improvement in microsomal stability. Furthermore, isotopically labeled glucose tracing revealed that picolinic acid 23 does not function by hexokinase inhibition. Thus, we report a new probe scaffold to interrogate dual-stage inhibition of T. gondii.