The lipid flippase ATP8A1 regulates the recruitment of ARF effectors to the trans-Golgi Network.

Formation of transport vesicles requires the coordinate activity of the coating machinery that selects cargo into the nascent vesicle and the membrane bending machinery that imparts curvature to the forming bud. Vesicle coating at the trans-Golgi Network (TGN) involves AP1, GGA2 and clathrin, which are recruited to membranes by activated ARF GTPases. The ARF activation at the TGN is mediated by the BIG1 and BIG2 guanine nucleotide exchange factors (GEFs). Membrane deformation at the TGN has been shown to be mediated by lipid flippases, including ATP8A1, that moves phospholipids from the inner to the outer leaflet of the TGN membrane. We probed a possible coupling between the coating and deformation machineries by testing for an interaction between BIG1, BIG2 and ATP8A1, and by assessing whether such an interaction may influence coating efficiency. Herein, we document that BIG1 and BIG2 co-localize with ATP8A1 in both, static and highly mobile TGN elements, and that BIG1 and BIG2 bind ATP8A1. We show that the interaction involves the catalytic Sec7 domain of the GEFs and the cytosolic C-terminal tail of ATP8A1. Moreover, we report that the expression of ATP8A1, but not ATP8A1 lacking the GEF-binding cytosolic tail, increases the generation of activated ARFs at the TGN and increases the selective recruitment of AP1, GGA2 and clathrin to TGN membranes. This occurs without increasing BIG1 or BIG2 levels at the TGN, suggesting that the binding of the ATP8A1 flippase tail to the Sec7 domain of BIG1/BIG2 increases their catalytic activity. Our results support a model in which a flippase component of the deformation machinery impacts the activity of the GEF component of the coating machinery.

Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.

The glutamate delta family of receptors is composed of GluD1 and GluD2 and serve as synaptic organizers. We have previously demonstrated several autism-like molecular and behavioral phenotypes including an increase in dendritic spines in GluD1 knockout mice. Based on previous reports we evaluated whether disruption of autophagy mechanisms may account for these phenotypes. Mouse model with conditional deletion of GluD1 from excitatory neurons in the corticolimbic regions was utilized. GluD1 loss led to overactive Akt-mTOR pathway, higher p62 and a lower LC3-II/LC3-I ratio in the somatosensory cortex suggesting reduced autophagy. Excitatory elements were increased in number but had immature phenotype based on puncta size, lower AMPA subunit GluA1 expression and impaired development switch from predominantly GluN2B to mixed GluN2A/GluN2B subunit expression. Overactive Akt-mTOR signaling and impaired autophagy was also observed in dorsal striatum upon conditional ablation of GluD1 and in the prefrontal cortex and hippocampus in constitutive knockout. Finally, cognitive deficits in novel object recognition test and fear conditioning were observed in mice with conditional ablation of GluD1 from the corticolimbic regions. Together, these results demonstrate a novel function of GluD1 in the regulation of autophagy pathway which may underlie autism phenotypes and is relevant to the genetic association of GluD1 coding, GRID1 gene with autism and other developmental disorders.

The ARF guanine nucleotide exchange factor GBF1 is targeted to Golgi membranes through a PIP-binding domain.

ADP-ribosylation factors (ARF) GTPases are activated by guanine nucleotide exchange factors (GEFs) to support cellular homeostasis. Key to understanding spatio-temporal regulation of ARF signaling is the mechanism of GEF recruitment to membranes. Small GEFs are recruited through phosphoinositide (PIP) binding by a pleckstrin homology (PH) domain downstream from the catalytic Sec7 domain (Sec7d). The large GEFs lack PH domains, and their recruitment mechanisms are poorly understood. We probed Golgi recruitment of GBF1, a GEF catalyzing ARF activation required for Golgi homeostasis. We show that the homology downstream of Sec7d-1 (HDS1) regulates Golgi recruitment of GBF1. We document that GBF1 binds phosphoinositides, preferentially PI3P, PI4P and PI(4,5)P2, and that lipid binding requires the HDS1 domain. Mutations within HDS1 that reduce GBF1 binding to specific PIPs in vitro inhibit GBF1 targeting to Golgi membranes in cells. Our data imply that HDS1 and PH domains are functionally analogous in that each uses lipid-based membrane information to regulate GEF recruitment. Lipid-based recruitment of GBF1 extends the paradigm of lipid regulation to small and large GEFs and suggests that lipid-based mechanisms evolved early during GEF diversification. This article has an associated First Person interview with the first author of the paper.

Oligomerization of the Sec7 domain Arf guanine nucleotide exchange factor GBF1 is dispensable for Golgi localization and function but regulates degradation.

Members of the large Sec7 domain-containing Arf guanine nucleotide exchange factor (GEF) family have been shown to dimerize through their NH2-terminal dimerization and cyclophilin binding (DCB) and homology upstream of Sec7 (HUS) domains. However, the importance of dimerization in GEF localization and function has not been assessed. We generated a GBF1 mutant (91/130) in which two residues required for oligomerization (K91 and E130 within the DCB domain) were replaced with A and assessed the effects of these mutations on GBF1 localization and cellular functions. We show that 91/130 is compromised in oligomerization but that it targets to the Golgi in a manner indistinguishable from wild-type GBF1 and that it rapidly exchanges between the cytosolic and membrane-bound pools. The 91/130 mutant appears active as it integrates within the functional network at the Golgi, supports Arf activation and COPI recruitment, and sustains Golgi homeostasis and cargo secretion when provided as a sole copy of functional GBF1 in cells. In addition, like wild-type GBF1, the 91/130 mutant supports poliovirus RNA replication, a process requiring GBF1 but believed to be independent of GBF1 catalytic activity. However, oligomerization appears to stabilize GBF1 in cells, and the 91/130 mutant is degraded faster than the wild-type GBF1. Our data support a model in which oligomerization is not a key regulator of GBF1 activity but impacts its function by regulating the cellular levels of GBF1.

Effect of ifenprodil on GluN1/GluN2B N-methyl-D-aspartate receptor gating.

Ifenprodil is an allosteric inhibitor of GluN1/GluN2B N-methyl-D-aspartate receptors. Despite its widespread use as a prototype for drug development and a subtype-selective tool for physiologic experiments, its precise effect on GluN1/GluN2B gating is yet to be fully understood. Interestingly, recent crystallographic evidence identified that ifenprodil, unlike zinc, binds at the interface of the GluN1/GluN2B amino terminal domain dimer by an induced-fit mechanism. To delineate the effect of this unique binding on GluN1/GluN2B receptor gating, we recorded steady-state currents from cell-attached and outside-out patches. At pH 7.9 in cell-attached patches, ifenprodil increased the occupancy of the long-lived shut conformations, thereby reducing the open probability of the receptor with no change in the mean open time. In addition, ifenprodil selectively affected the area of shut time constants, but not the time constants themselves. Kinetic analyses suggested that ifenprodil prevents the transition of the receptor to an open state and increases its dwell time in an intrinsically occurring closed conformation or desensitized state. We found distinct differences in the action of ifenprodil at GluN1/GluN2B in comparison with previous studies on the effect of zinc on GluN1/GluN2A gating, which may arise due to their unique binding sites. Our data also uncover the potential pH-dependent action of ifenprodil on gating. At a low pH (pH 7.4), but not pH 7.9, ifenprodil reduces the mean open time of GluN1/GluN2B receptors, which may be responsible for its usefulness as a context-dependent inhibitor in conditions like ischemia and stroke, when the pH of the extracellular milieu becomes acidic.

Glutamate delta-1 receptor regulates oligodendrocyte progenitor cell differentiation and myelination in normal and demyelinating conditions.

In this study, we investigated the role of glutamate delta 1 receptor (GluD1) in oligodendrocyte progenitor cell (OPC)-mediated myelination during basal (development) and pathophysiological (cuprizone-induced demyelination) conditions. Initially, we sought to determine the expression pattern of GluD1 in OPCs and found a significant colocalization of GluD1 puncta with neuron-glial antigen 2 (NG2, OPC marker) in the motor cortex and dorsal striatum. Importantly, we found that the ablation of GluD1 led to an increase in the number of myelin-associated glycoprotein (MAG+) cells in the corpus callosum and motor cortex at P40 without affecting the number of NG2+ OPCs, suggesting that GluD1 loss selectively facilitates OPC differentiation rather than proliferation. Further, deletion of GluD1 enhanced myelination in the corpus callosum and motor cortex, as indicated by increased myelin basic protein (MBP) staining at P40, suggesting that GluD1 may play an essential role in the developmental regulation of myelination during the critical window period. In contrast, in cuprizone-induced demyelination, we observed reduced MBP staining in the corpus callosum of GluD1 KO mice. Furthermore, cuprizone-fed GluD1 KO mice showed more robust motor deficits. Collectively, our results demonstrate that GluD1 plays a critical role in OPC regulation and myelination in normal and demyelinating conditions.

The Arf-GEF GBF1 undergoes multi-domain structural shifts to activate Arf at the Golgi.

Golgi homeostasis require the activation of Arf GTPases by the guanine-nucleotide exchange factor requires GBF1, whose recruitment to the Golgi represents a rate limiting step in the process. GBF1 contains a conserved, catalytic, Sec7 domain (Sec7d) and five additional (DCB, HUS, HDS1-3) domains. Herein, we identify the HDS3 domain as essential for GBF1 membrane association in mammalian cells and document the critical role of HDS3 during the development of Drosophila melanogaster. We show that upon binding to Golgi membranes, GBF1 undergoes conformational changes in regions bracketing the catalytic Sec7d. We illuminate GBF1 interdomain arrangements by negative staining electron microscopy of full-length human GBF1 to show that GBF1 forms an anti-parallel dimer held together by the paired central DCB-HUS core, with two sets of HDS1-3 arms extending outward in opposite directions. The catalytic Sec7d protrudes from the central core as a largely independent domain, but is closely opposed to a previously unassigned α-helix from the HDS1 domain. Based on our data, we propose models of GBF1 engagement on the membrane to provide a paradigm for understanding GBF1-mediated Arf activation required for cellular and organismal function.

Persistence of choking injuries in children.

BACKGROUND: Choking injuries are a significant cause of morbidity and mortality in children and represent a significant public health concern. Evaluating trends and the impact of interventions are essential to highlight whether progress has been made and to target public health efforts. OBJECTIVE: To investigate how rates of nonfatal and fatal choking injuries have changed before and after 2010 when policy recommendations were made by the American Academy of Pediatrics. METHODS: A descriptive study investigating unintentional nonfatal and fatal choking injuries in children aged 0-19 years using national data from 2001 to 2016 through the Centers for Disease Control and Prevention's WISQARS™ and WONDER databases, focusing on the 6 years prior and 6 years after release of the AAP's recommendations. The data was categorized by age, gender, year, and race/ethnicity for descriptive and statistical analyses. RESULTS: From 2001 to 2016, there were a total of 305,814 nonfatal injuries and 2347 choking deaths in children from 0 to 19 years. Children under five years of age accounted for 73% of nonfatal injuries and 75% of choking fatalities. There was a statistically significant increase in the nonfatal injuries rate when comparing 2005-2010 and 2011-2016 (19/100,000 versus 26/100,000, respectively). There was a decrease in the choking fatalities rate in all children (0.18/100,000 versus 0.16/100,000, respectively) but no change in fatalities rate for children under five. White and Black children experience nonfatal choking injuries at a higher rate than Hispanics. Black children had highest rates of choking fatalities over Hispanic, White, Asian, and Alaskan or American Indian ethnicities. The lowest rates of death occurred in Asians. CONCLUSIONS: Overall rate of nonfatal choking injuries increased, while rate of choking fatalities in children decreased after 2010. However, the choking fatalities rate in 0-4 years olds, the highest risk group, did not change. Racial gaps exist with highest rates of injury in Black children. We must continue to educate and raise awareness of choking injuries, with targeted efforts to address racial disparities.

Current Approaches for Integrating Responsible and Ethical Conduct of Research (RECR) Education into Course-based Undergraduate Research Experiences: A National Assessment.

Course-based undergraduate research experiences (CUREs), which often engage students as early as freshman year, have become increasingly common in biology curricula. While many studies have highlighted the benefits of CUREs, little attention has been paid to responsible and ethical conduct of research (RECR) education in such contexts. Given this observation, we adopted a mixed methods approach to explore the extent to which RECR education is being implemented and assessed in biological sciences CUREs nationwide. Survey and semistructured interview data show a general awareness of the importance of incorporating RECR education into CUREs, with all respondents addressing at least one RECR topic in their courses. However, integration of RECR education within the CURE environment primarily focuses on the application of RECR during research practice, often takes the form of corrective measures, and appears to be rarely assessed. Participants reported lack of time and materials as the main barriers to purposeful inclusion of RECR education within their courses. These results underscore a need for the CURE community to develop resources and effective models to integrate RECR education into biology CUREs.

Epidemiology and gender differences in pediatric recreational and firearms noise exposure in the USA.

OBJECTIVE: We aim to identify contemporary noise exposures and hearing protection use among U.S. children in a large, population-based study. METHODS: Cross-sectional analysis of the 2014 National Health Interview Series was performed. Results from in-person interviews of families with children under 18 years of age in all 50 states were queried. Potentially harmful exposures to loud sounds and patterns of hearing protection use in the last 12 months were analyzed after representative sample weights were applied. RESULTS: Among 73.4 million children, 18.4% (9.1 ± 0.4 million) (boys: 23.2%, girls: 13.5%; P < 0.001) were exposed to firearms noise, and 28.2% (20.7 ± 0.6 million) (boys: 30.5%, girls: 25.8%; P < 0.001) to firecrackers and other explosive sounds. Exposure to recreational "very-loud" noise exposure was more common (7.9%; 5.8 ± 0.3 million), consisting of music players (46.5%), fireworks (44.8%), lawnmowers (42.6%), and firearms (32.5%). However, only 17.1% of boys and 15.6% of girls, totaling 16.4% of all children, always used hearing protection during noise exposures. CONCLUSION: Children in the United States are commonly exposed to firearms and recreational loud noises. Hearing protection is infrequently used, and gender disparities in patterns of exposure and use of hearing protection are prevalent. Those children and families at risk should be identified via public health initiatives and appropriately counseled by healthcare providers. LEVEL OF EVIDENCE: NA Laryngoscope, 130:541-545, 2020.

Demonstrating the benefits of a multidisciplinary aerodigestive program.

OBJECTIVES/HYPOTHESIS: The Aerodigestive Program (the Aero Program) at Children's Hospital Colorado is a multidisciplinary program focused on airway, digestive, and lung disorders in complex children, involving collaboration between gastroenterology, pulmonology, anesthesiology, and otolaryngology in clinic and operating room. These programs have proliferated as institutions focus on providing greater care coordination and family satisfaction. However, few cost, charge, and satisfaction data exist to support these resource-intensive programs. The goal of this study was to investigate the value of combined triple endoscopy delivered by the Aero Program through analysis of institutional charges, direct costs, operating room efficiency metrics, and parent satisfaction. STUDY DESIGN: Program evaluation. METHODS: Finance, satisfaction, efficiency, and quality-of-care metrics were evaluated within and outside of the Aero Program through retrospective queries of electronic health records, administrative databases, and parent surveys at our institution. RESULTS: Mean anesthesia time in the Aero Program was 54 minutes (49-60; 95% confidence interval), which was significantly less (P < .0001) than the estimated 89 minutes of having the three procedures done separately. Average charges and average direct costs for triple endoscopy were 38.8% and 41.9% less than the sum of the averages for separate procedures, respectively. Parent satisfaction was high for the Aero Program care. CONCLUSIONS: As organizations move toward greater coordination of care for complex patients, multidisciplinary programs must demonstrate their value by delivering cost-effective care. Aerodigestive programs have the potential to provide satisfying care that is less costly to the organization, insurer, and family. These programs represent a step in the evolution toward higher value care and value-based payment methodology. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:521-525, 2020.

Rhinosinusitis in Pediatric Primary Ciliary Dyskinesia: Impact of Disease.

OBJECTIVES: Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by abnormal respiratory cilia ultrastructure and/or function causing defective mucociliary clearance. We investigated the extent and severity of rhinosinusitis in a large cohort of children with PCD and explored associations among risk factors, including genotype and sinus disease. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic children's hospital. SUBJECTS AND METHODS: A review was conducted with a patient registry at the PCD Foundation Center at our institution. Demographic, imaging, clinical, and operative data were reviewed through the institutional electronic health record system. RESULTS: Fifty-four subjects were identified with mean and median age at diagnosis of 5.2 and 4.0 years. The male:female ratio was 35%:65%. Sinus symptoms were present in 46 (85%) subjects, 22 of whom had chronic rhinosinusitis. Nineteen (35%) subjects underwent operative intervention, consisting of endoscopic sinus surgery (ESS; 16 patients) and maxillary lavage (3 patients). Nineteen subjects underwent adenoidectomy for PCD-related indications. Five sinus-related admissions in 3 subjects were noted during the study period, and no complication of rhinosinusitis occurred in the cohort. Genetic test results were available in 27 subjects, in whom 23 (85%) had biallelic mutations in a PCD gene. Demographic factors, Lund-Mackay score, and PCD genotype were not found to be predictors for ESS or hospitalization in our cohort. CONCLUSION: While rhinosinusitis was common in our PCD cohort, most patients did not require ESS. Since complications of rhinosinusitis were uncommon, we recommend judicious surgical management tailored to the patient's symptoms.

MitCHAP-60 and Hereditary Spastic Paraplegia SPG-13 Arise from an Inactive hsp60 Chaperonin that Fails to Fold the ATP Synthase ß-Subunit.

The human mitochondrial heat shock protein 60 (hsp60) is a tetradecameric chaperonin that folds proteins in the mitochondrial matrix. An hsp60 D3G mutation leads to MitCHAP-60, an early onset neurodegenerative disease while hsp60 V72I has been linked to SPG13, a form of hereditary spastic paraplegia. Previous studies have suggested that these mutations impair the protein folding activity of hsp60 complexes but the detailed mechanism by which these mutations lead the neuromuscular diseases remains unknown. It is known, is that the ß-subunit of the human mitochondrial ATP synthase co-immunoprecipitates with hsp60 indicating that the ß-subunit is likely a substrate for the chaperonin. Therefore, we hypothesized that hsp60 mutations cause misfolding of proteins that are critical for aerobic respiration. Negative-stain electron microscopy and DLS results suggest that the D3G and V72I complexes fall apart when treated with ATP or ADP and are therefore unable to fold denatured substrates such as α-lactalbumin, malate dehydrogenase (MDH), and the ß-subunit of ATP synthase in in-vitro protein-folding assays. These data suggests that hsp60 plays a crucial role in folding important players in aerobic respiration such as the ß-subunit of the ATP synthase. The hsp60 mutations D3G and V72I impair its ability to fold mitochondrial substrates leading to abnormal ATP synthesis and the development of the MitCHAP-60 and SPG13 neuromuscular degenerative disorders.

Promiscuity of the catalytic Sec7 domain within the guanine nucleotide exchange factor GBF1 in ARF activation, Golgi homeostasis, and effector recruitment.

The integrity of the Golgi and trans-Golgi network (TGN) is disrupted by brefeldin A (BFA), which inhibits the Golgi-localized BFA-sensitive factor (GBF1) and brefeldin A-inhibited guanine nucleotide-exchange factors (BIG1 and BIG2). Using a cellular replacement assay to assess GBF1 functionality without interference from the BIGs, we show that GBF1 alone maintains Golgi architecture; facilitates secretion; activates ADP-ribosylation factor (ARF)1, 3, 4, and 5; and recruits ARF effectors to Golgi membranes. Unexpectedly, GBF1 also supports TGN integrity and recruits numerous TGN-localized ARF effectors. The impact of the catalytic Sec7 domain (Sec7d) on GBF1 functionality was assessed by swapping it with the Sec7d from ARF nucleotide-binding site opener (ARNO)/cytohesin-2, a plasma membrane GEF reported to activate all ARFs. The resulting chimera (GBF1-ARNO-GBF1 [GARG]) targets like GBF1, supports Golgi/TGN architecture, and facilitates secretion. However, unlike GBF1, GARG activates all ARFs (including ARF6) at the Golgi/TGN and recruits additional ARF effectors to the Golgi/TGN. Our results have general implications: 1) GEF's targeting is independent of Sec7d, but Sec7d influence the GEF substrate specificity and downstream effector events; 2) all ARFs have access to all membranes, but are restricted in their distribution by the localization of their activating GEFs; and 3) effector association with membranes requires the coincidental presence of activated ARFs and specific membrane identifiers.

Recommendations for Effective Integration of Ethics and Responsible Conduct of Research (E/RCR) Education into Course-Based Undergraduate Research Experiences: A Meeting Report.

Advancement of the scientific enterprise relies on individuals conducting research in an ethical and responsible manner. Educating emergent scholars in the principles of ethics/responsible conduct of research (E/RCR) is therefore critical to ensuring such advancement. The recent impetus to include authentic research opportunities as part of the undergraduate curriculum, via course-based undergraduate research experiences (CUREs), has been shown to increase cognitive and noncognitive student outcomes. Because of these important benefits, CUREs are becoming more common and often constitute the first research experience for many students. However, despite the importance of E/RCR in the research process, we know of few efforts to incorporate E/RCR education into CUREs. The Ethics Network for Course-based Opportunities in Undergraduate Research (ENCOUR) was created to address this concern and promote the integration of E/RCR within CUREs in the biological sciences and related disciplines. During the inaugural ENCOUR meeting, a four-pronged approach was used to develop guidelines for the effective integration of E/RCR in CUREs. This approach included: 1) defining appropriate student learning objectives; 2) identifying relevant curriculum; 3) identifying relevant assessments; and 4) defining key aspects of professional development for CURE facilitators. Meeting outcomes, including the aforementioned E/RCR guidelines, are described herein.

First Year Course-Based Undergraduate Research Experience (CURE) Using the CRISPR/Cas9 Genome Engineering Technology in Zebrafish.

Genetic analysis in model systems can provide a rich context for conceptual understanding of gene structure, regulation, and function. With an intent to create a rich learning experience in molecular genetics, we developed a semester-long course-based undergraduate research experience (CURE) using the CRISPR-Cas9 gene editing system to disrupt specific genes in the zebrafish. The course was offered to freshman students; nine students worked in four groups (two to three members per group) to design, synthesize, and test the nuclease activity of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/sgRNAs for targeted disruption of specific genes in the zebrafish. Each group worked with a gene with an already known mutant phenotype that can be visually scored and a gene that had not been studied in zebrafish previously. Embedded in the course were a series of workshop-styled units or tutorials, including tours to core facilities. The focus was on introducing and developing skills that could be accommodated within the span of a semester. Each group successfully cloned at least one plasmid-encoding CRISPR/sgRNA template, visually analyzed injected embryos, and performed genotyping assays to detect CRISPR-Cas9 activity. In-class discussions, a final end-of-semester written test, and group oral presentations were assessed for an understanding of the CRISPR-Cas9 system, application of the CRISPR-Cas9 system as a gene manipulation tool, and experimental methods used to create plasmid vectors and synthesize sgRNA. In addition, poster presentations were evaluated by faculty, graduate students, and senior undergraduate students at a University research exposition. Self-reflections in the form of group conversations were video recorded. All students (9/9) distinctly showed learning gains after completing the activity, but the extent of the gains was variable, as seen from results of a written test and poster presentation assessment. Qualitative analysis of evaluations and self-reporting data indicated several gains, suggesting that all students found many aspects of the CURE valuable and gained project-specific (conceptual) and transferrable skills (science process and science identity).

Single-Ring Intermediates Are Essential for Some Chaperonins.

Chaperonins are macromolecular complexes found throughout all kingdoms of life that assist unfolded proteins reach a biologically active state. Historically, chaperonins have been classified into two groups based on sequence, subunit structure, and the requirement for a co-chaperonin. Here, we present a brief review of chaperonins that can form double- and single-ring conformational intermediates in their protein-folding catalytic pathway. To date, the bacteriophage encoded chaperonins ϕ-EL and OBP, human mitochondrial chaperonin and most recently, the bacterial groEL/ES systems, have been reported to form single-ring intermediates as part of their normal protein-folding activity. These double-ring chaperonins separate into single-ring intermediates that have the ability to independently fold a protein. We discuss the structural and functional features along with the biological relevance of single-ring intermediates in cellular protein folding. Of special interest are the ϕ-EL and OBP chaperonins which demonstrate features of both group I and II chaperonins in addition to their ability to function via single-ring intermediates.

Relationships between tinnitus and the prevalence of anxiety and depression.

OBJECTIVES/HYPOTHESIS: Quantify the relationships between tinnitus, and anxiety and depression among adults. STUDY DESIGN: Cross-sectional analysis of a national health survey. METHODS: Adult respondents in the 2007 Integrated Health Interview Series tinnitus module were analyzed. Data for tinnitus symptoms and severity and reported anxiety and depression symptoms were extracted. Associations between tinnitus problems and anxiety, depression, lost workdays, days of alcohol consumption, and mean hours of sleep were assessed. RESULTS: Among 21.4 ± 0.69 million adult tinnitus sufferers, 26.1% reported problems with anxiety in the preceding 12 months, whereas only 9.2% of those without tinnitus reported an anxiety problem (P < .001). Similarly, 25.6% of respondents with tinnitus reported problems with depression, whereas only 9.1% of those without tinnitus reported depression symptoms (P < .001). Those reporting tinnitus symptoms as a "big" or "very big" problem were more likely to concurrently report anxiety (odds ratio [OR]: 5.7; 95% CI: 4.0-8.1; P < .001) and depression (OR: 4.8; 95% CI: 3.5-6.7; P < .001) symptoms. Tinnitus sufferers reported significantly fewer mean hours of sleep per night (7.00 vs. 7.21; P < .001) and greater mean days of work missed (6.94 vs. 3.79, P < .001) compared to those who did not report tinnitus. Mean days of alcohol consumption between the two groups were not significantly different. CONCLUSIONS: Tinnitus symptoms are closely associated with anxiety, depression, shorter sleep duration, and greater workdays missed. These comorbidities and sequelae should be recognized and addressed to optimally manage patients with chronic and bothersome tinnitus. LEVEL OF EVIDENCE: 4 Laryngoscope, 2016 127:466-469, 2017.

Epidemiology of firearm and other noise exposures in the United States.

OBJECTIVE: Identify contemporary noise exposures and hearing protection use among adults. STUDY DESIGN: Cross-sectional analysis of national health survey. METHODS: Adult respondents in the 2014 National Health Interview Series hearing survey module were analyzed. Potentially harmful exposures to occupational and recreational noises in the past 12 months were extracted and quantified. Patterns of hearing protection use also were analyzed. RESULTS: Among 239.7 million adults, "loud" and "very loud" occupational noise exposures were reported by 5.3% and 21.7%, respectively. Of those exposed to "loud" or "very loud" sounds at work, only 18.7% and 43.6%, respectively, always used hearing protection. A total of 38.2% (1.9 million) of those with "very loud" occupational exposures never used hearing protection. Frequent (> 10/year) "loud" and "very loud" recreational noise exposures were reported by 13.9% and 21.1%, respectively, most commonly to lawn mowers (72.6% and 55.2%, respectively). When exposed to recreational "loud/very loud" noise, only 11.4% always used hearing protection, whereas 62.3% (6.3 million) never used any protection. Lifetime exposure to firearm noise was reported by 36.6% of adults, 11.5% of whom had used firearms in the prior 12 months. Of those, only 58.5% always used hearing protection, whereas 21.4% (7.4 million) never used hearing protection. CONCLUSION: Substantial noise exposures with potentially serious long-term hearing health consequences frequently are occurring in occupational and recreational settings, and with the use of firearms. Only a minority of those exposed consistently are using hearing protection. Healthcare providers should actively identify and encourage the use of hearing protection with those patients at risk. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:E340-E346, 2017.

Dosimetric Analysis of Neural and Vascular Structures in Skull Base Tumors Treated with Stereotactic Radiosurgery.

Objective To examine the relationship between the prescribed target dose and the dose to healthy neurovascular structures in patients with vestibular schwannomas treated with stereotactic radiosurgery (SRS). Study Design Case series with chart review. Setting SRS center from 2011 to 2013. Subjects Twenty patients with vestibular schwannomas treated at the center from 2011 to 2013. Methods Twenty patients with vestibular schwannomas were included. The average radiation dose delivered to healthy neurovascular structures (eg, carotid artery, basilar artery, facial nerve, trigeminal nerve, and cochlea) was analyzed. Results Twenty patients with vestibular schwannomas who were treated with fused computed tomography/magnetic resonance imaging-guided SRS were included in the study. The prescribed dose ranged from 10.58 to 17.40 Gy over 1 to 3 hypofractions to cover 95% of the target tumor volume. The mean dose to the carotid artery was 5.66 Gy (95% confidence interval [CI], 4.53-6.80 Gy), anterior inferior cerebellar artery was 8.70 Gy (95% CI, 4.54-12.86 Gy), intratemporal facial nerve was 3.76 Gy (95% CI, 3.04-4.08 Gy), trigeminal nerve was 5.21 Gy (95% CI, 3.31-7.11 Gy), and the cochlea was 8.70 Gy (95% CI, 7.81-9.59 Gy). Conclusions SRS for certain vestibular schwannomas can expose the anterior inferior cerebellar artery (AICA) and carotid artery to radiation doses that can potentially initiate atherosclerotic processes. The higher doses to the AICA and carotid artery correlated with increasing tumor volume. The dose delivered to other structures such as the cochlea and intratemporal facial nerve appears to be lower and much less likely to cause immediate complications when shielded.