Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.

Biased placement of Mitochondria fission facilitates asymmetric inheritance of protein aggregates during yeast cell division.

Mitochondria are essential and dynamic eukaryotic organelles that must be inherited during cell division. In yeast, mitochondria are inherited asymmetrically based on quality, which is thought to be vital for maintaining a rejuvenated cell population; however, the mechanisms underlying mitochondrial remodeling and segregation during this process are not understood. We used high spatiotemporal imaging to quantify the key aspects of mitochondrial dynamics, including motility, fission, and fusion characteristics, upon aggregation of misfolded proteins in the mitochondrial matrix. Using these measured parameters, we developed an agent-based stochastic model of dynamics of mitochondrial inheritance. Our model predicts that biased mitochondrial fission near the protein aggregates facilitates the clustering of protein aggregates in the mitochondrial matrix, and this process underlies asymmetric mitochondria inheritance. These predictions are supported by live-cell imaging experiments where mitochondrial fission was perturbed. Our findings therefore uncover an unexpected role of mitochondrial dynamics in asymmetric mitochondrial inheritance.

Suppression of chromosome instability by targeting a DNA helicase in budding yeast.

Chromosome instability (CIN) is an important driver of cancer initiation, progression, drug resistance, and aging. As such, genes whose inhibition suppresses CIN are potential therapeutic targets. We report here that deletion of an accessory DNA helicase, Rrm3, suppresses high CIN caused by a wide range of genetic or pharmacological perturbations in yeast. Although this helicase mutant has altered cell cycle dynamics, suppression of CIN by rrm3∆ is independent of the DNA damage and spindle assembly checkpoints. Instead, the rrm3∆ mutant may have increased kinetochore-microtubule error correction due to an altered localization of Aurora B kinase and associated phosphatase, PP2A-Rts1.

Successful decannulation of patients with traumatic spinal cord injury: A scoping review.

Context: Patients with spinal cord injury (SCI) often require tracheostomy as an immediate life-saving measure. Successful decannulation, or removal of the tracheostomy, improves patient quality of life, function, and physical appearance and is considered an important rehabilitative milestone for SCI patients.Objective: We sought to synthesize the existing published literature on SCI patients undergoing decannulation.Methods: Ovid MEDLINE, Embase, Web of Science, CINAHL, and Cochrane Central Register of Controlled Trials were systematically searched through July 2, 2019 using appropriate keywords and MeSH terms pertaining to tracheostomy and SCI. Searches were human-subject only without language restrictions. Published literature discussing the outcomes of SCI patients who underwent decannulation were screened using inclusion/exclusion criteria determined a priori and reviewed.Results: Twenty-six publications were eligible for review and synthesis out of 1,493 unique articles. Over half of the studies were retrospective case series or reports. The research was nearly all published within the fields of physical medicine and rehabilitation, neurology, and pulmonary/critical care. Three themes emerged from review: (1) interdisciplinary or multidisciplinary tracheostomy team management to optimize decannulation processes, (2) non-invasive intermittent positive-pressure ventilatory support instead of tracheostomy-based ventilator support, and (3) wide variation in the reporting of post-decannulation clinical outcomes.Conclusion: Published research lacks a consistent taxonomy for reporting post-decannulation outcomes in SCI patients. Non-invasive ventilation research could benefit many SCI patients but has been studied in depth primarily by a single authorship group. Further investigation into the socioeconomic and fiscal impact on tracheostomies on SCI patients is warranted.

Input-specific modulation of murine nucleus accumbens differentially regulates hedonic feeding.

Hedonic feeding is driven by the "pleasure" derived from consuming palatable food and occurs in the absence of metabolic need. It plays a critical role in the excessive feeding that underlies obesity. Compared to other pathological motivated behaviors, little is known about the neural circuit mechanisms mediating excessive hedonic feeding. Here, we show that modulation of prefrontal cortex (PFC) and anterior paraventricular thalamus (aPVT) excitatory inputs to the nucleus accumbens (NAc), a key node of reward circuitry, has opposing effects on high fat intake in mice. Prolonged high fat intake leads to input- and cell type-specific changes in synaptic strength. Modifying synaptic strength via plasticity protocols, either in an input-specific optogenetic or non-specific electrical manner, causes sustained changes in high fat intake. These results demonstrate that input-specific NAc circuit adaptations occur with repeated exposure to a potent natural reward and suggest that neuromodulatory interventions may be therapeutically useful for individuals with pathologic hedonic feeding.

Solid-phase inclusion as a mechanism for regulating unfolded proteins in the mitochondrial matrix.

Proteostasis declines with age, characterized by the accumulation of unfolded or damaged proteins. Recent studies suggest that proteins constituting pathological inclusions in neurodegenerative diseases also enter and accumulate in mitochondria. How unfolded proteins are managed within mitochondria remains unclear. Here, we found that excessive unfolded proteins in the mitochondrial matrix of yeast cells are consolidated into solid-phase inclusions, which we term deposits of unfolded mitochondrial proteins (DUMP). Formation of DUMP occurs in mitochondria near endoplasmic reticulum-mitochondria contact sites and is regulated by mitochondrial proteins controlling the production of cytidine 5'-diphosphate-diacylglycerol. DUMP formation is age dependent but accelerated by exogenous unfolded proteins. Many enzymes of the tricarboxylic acid cycle were enriched in DUMP. During yeast cell division, DUMP formation is necessary for asymmetric inheritance of damaged mitochondrial proteins between mother and daughter cells. We provide evidence that DUMP-like structures may be induced by excessive unfolded proteins in human cells.

Comparison of Referral Pathways in Otolaryngology at a Public Versus Private Academic Center.

OBJECTIVE: Delayed medical care may be costly and dangerous. Examining referral pathways may provide insight into ways to reduce delays in care. We sought to compare time between initial referral and first clinic visit and referral and surgical intervention for index otolaryngologic procedures between a public safety net hospital (PSNH) and tertiary-care academic center (TAC). METHODS: Retrospective cohort study of eligible adult patients undergoing one of several general otolaryngologic procedures at a PSNH (n = 216) and a TAC (n = 161) over a 2-year time period. RESULTS: PSNH patients were younger, less likely to have comorbidities and more likely to be female, Hispanic or Asian, and to lack insurance. Time between referral and first clinic visit was shorter at the PSNH than the TAC (Mean 35.8 ± 47.7 vs 48.3 ± 60.3 days; P = .03). Time between referral and surgical intervention did not differ between groups (129 ± 90 for PSNH vs 141 ± 130 days for TAC, P = .30). On multivariate analysis, the TAC had more patient-related delays in care than the PSNH (OR: 3.75, P < .001). Time from referral to surgery at a PSNH was associated with age, source of referral, type of surgery, diagnostic workup and comorbidities, and at a TAC was associated with gender and type of surgery and comorbidities. CONCLUSIONS: Sociodemographic differences between PSNH and TAC patients, as well as differences in referral pathways between the types of institutions, influence progression of surgical care in otolaryngology. These differences may be targets for interventions to streamline care. LEVEL OF EVIDENCE: 2c.

Endophthalmitis rates among patients receiving intravitreal anti-VEGF injections: a USA claims analysis.

PURPOSE: Intravitreal (IVT) injections of the anti-vascular endothelial growth factor (VEGF) agents aflibercept, bevacizumab, and ranibizumab are commonly prescribed to treat neovascular age-related macular degeneration (nAMD). Studies comparing inflammation rates in large populations of patients receiving these agents and the treatment of ocular inflammation post-IVT anti-VEGF injections are scarce. In this study, we compared rates of endophthalmitis claims (sterile and infectious) following IVT anti-VEGF injections to determine the risk factors associated with developing endophthalmitis, and examined the claims for subsequent treatment. PATIENTS AND METHODS: This retrospective cohort study of USA claims data examined the risk of developing endophthalmitis following IVT injection of aflibercept, bevacizumab, or ranibizumab in patients with nAMD between 11/18/2011 and 5/31/2013. The primary study outcome was occurrence of endophthalmitis within 30 days of a claim for an IVT anti-VEGF injection. Endophthalmitis rates were calculated separately for aflibercept, bevacizumab, and ranibizumab, followed by pairwise comparisons of endophthalmitis frequencies among the 3 treatments. RESULTS: This analysis included 818,558 injections from 156,594 patients with nAMD. The rates (% [n/N]) of endophthalmitis following aflibercept, bevacizumab, and ranibizumab IVT injections were 0.100% (136/135,973), 0.056% (268/481,572), and 0.047% (94/201,013), respectively. In a multivariate analysis, aflibercept was associated with a significantly higher risk of endophthalmitis vs ranibizumab (adjusted odds ratio, 2.19; 95% CI: 1.68-2.85; P<0.0001). The risk of endophthalmitis was similar for bevacizumab and ranibizumab. Within 14 days after endophthalmitis, 38.6% of cases received injectable antibiotics, 15.3% received injectable steroids, and 30.3% underwent vitrectomy. CONCLUSION: The rate of endophthalmitis was very low, but higher following IVT injection with aflibercept compared with both bevacizumab and ranibizumab in patients with nAMD.

Cost-Effectiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States.

PURPOSE: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (FIRE-3) data to evaluate clinical and economic tradeoffs associated with first-line treatments of KRAS wild-type (WT) metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab. Hypothetical KRAS-WT mCRC patients initiated first-line treatment and could experience adverse events, disease progression warranting second-line treatment, or clinical response and hepatic metastasectomy. Model inputs were derived from FIRE-3 and published literature. Incremental cost-effectiveness ratios (ICERs) were reported as US$ per life year (LY) and quality-adjusted life year (QALY). Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data; 1-way and probabilistic sensitivity analyses were conducted. RESULTS: Compared with bevacizumab, KRAS-WT patients receiving first-line cetuximab gained 5.7 months of life at a cost of $46,266, for an ICER of $97,223/LY ($122,610/QALY). For extended RAS-WT patients, the ICER was $77,339/LY ($99,584/QALY). Cetuximab treatment was cost-effective 80.3% of the time, given a willingness-to-pay threshold of $150,000/LY. Results were sensitive to changes in survival, treatment duration, and product costs. CONCLUSIONS: Our analysis of FIRE-3 data suggests that first-line treatment with cetuximab and FOLFIRI in KRAS (and extended RAS) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI. This information, in combination with other studies investigating comparative effectiveness of first-line options, can be useful to clinicians, payers, and policymakers in making treatment and resource allocation decisions for mCRC patients.

Who's Managing Otolaryngologic Conditions in the United States?

Growth of an aging US population, coupled with implementation of the Patient Protection and Affordable Care Act, will pose logistical challenges for the primary care provider (PCP) workforce for the foreseeable future. In particular, the burden of otolaryngologic care placed on PCPs is substantial, based on research dating back to the 1970s and confirmed by a recent analysis of the US National Ambulatory Medical Care Survey. Collaboration between the otolaryngology and primary care communities will be needed to ensure that PCPs gain adequate exposure and training in routine otolaryngology care to improve the clinical management of ear, nose, and throat conditions in an expanding population.

CARE guidelines for case reports: explanation and elaboration document.

BACKGROUND: Well-written and transparent case reports (1) reveal early signals of potential benefits, harms, and information on the use of resources; (2) provide information for clinical research and clinical practice guidelines, and (3) inform medical education. High-quality case reports are more likely when authors follow reporting guidelines. During 2011-2012, a group of clinicians, researchers, and journal editors developed recommendations for the accurate reporting of information in case reports that resulted in the CARE (CAse REport) Statement and Checklist. They were presented at the 2013 International Congress on Peer Review and Biomedical Publication, have been endorsed by multiple medical journals, and translated into nine languages. OBJECTIVES: This explanation and elaboration document has the objective to increase the use and dissemination of the CARE Checklist in writing and publishing case reports. ARTICLE DESIGN AND SETTING: Each item from the CARE Checklist is explained and accompanied by published examples. The explanations and examples in this document are designed to support the writing of high-quality case reports by authors and their critical appraisal by editors, peer reviewers, and readers. RESULTS AND CONCLUSION: This article and the 2013 CARE Statement and Checklist, available from the CARE website [www.care-statement.org] and the EQUATOR Network [www.equator-network.org], are resources for improving the completeness and transparency of case reports.

Prevalence and Outcomes of Head and Neck versus Non-Head and Neck Second Primary Malignancies in Head and Neck Squamous Cell Carcinoma: An Analysis of the Surveillance, Epidemiology, and End Results Database.

BACKGROUND/AIMS: Patients with head and neck squamous cell carcinoma (HNSCC) are at risk for second primary malignancies (SPMs). The prevalence, distribution, and patient survival in head and neck versus non-head and neck SPMs are not fully elucidated. The objective of this study was to quantify the rate of SPMs in patients with HNSCC. METHODS: This is a population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Prevalence and location of SPMs, and survival data were analyzed. RESULTS: There were 58,363 HNSCC patients, and the prevalence of HNSCC and non-HNSCC SPMs was 3.0% (1,746) and 8.8% (5,109), respectively. Overall survival (OS) was higher in patients with HNSCC SPMs compared to non-HNSCC SPMs (p < 0.001), with no difference in disease-specific survival. Patients with SPMs in the lung and esophagus had a worse OS (p < 0.001), and patients with SPMs in the prostate and breast had a better OS (p < 0.001). CONCLUSION: In HNSCC patients who develop SPMs, nearly 75% are non-HNSCC SPMs. Patients with non-HNSCC SPMs have a lower OS. Future clinical practice guidelines should take the risks and locations of SPM development into consideration for screening.

Input- and Output-Specific Regulation of Serial Order Performance by Corticostriatal Circuits.

The serial ordering of individual movements into sequential patterns is thought to require synaptic plasticity within corticostriatal circuits that route information through the basal ganglia. We used genetically and anatomically targeted manipulations of specific circuit elements in mice to isolate the source and target of a corticostriatal synapse that regulates the performance of a serial order task. This excitatory synapse originates in secondary motor cortex, terminates on direct pathway medium spiny neurons in the dorsolateral striatum, and is strengthened by serial order learning. This experience-dependent and synapse-specific form of plasticity may sculpt the balance of activity in basal ganglia circuits during sequential movements, driving a disparity in striatal output that favors the direct pathway. This disparity is necessary for execution of responses in serial order, even though both direct and indirect pathways are active during movement initiation, suggesting dynamic modulation of corticostriatal circuitry contributes to the choreography of behavioral routines.

Single-Cell mRNA Profiling Reveals Cell-Type-Specific Expression of Neurexin Isoforms.

Neurexins are considered central organizers of synapse architecture that are implicated in neuropsychiatric disorders. Expression of neurexins in hundreds of alternatively spliced isoforms suggested that individual neurons might exhibit a cell-type-specific neurexin expression pattern (a neurexin code). To test this hypothesis, we quantified the single-cell levels of neurexin isoforms and other trans-synaptic cell-adhesion molecules by microfluidics-based RT-PCR. We show that the neurexin repertoire displays pronounced cell-type specificity that is remarkably consistent within each type of neuron. Furthermore, we uncovered region-specific regulation of neurexin transcription and splice-site usage. Finally, we demonstrate that the transcriptional profiles of neurexins can be altered in an experience-dependent fashion by exposure to a drug of abuse. Our data provide evidence of cell-type-specific expression patterns of multiple neurexins at the single-cell level and suggest that expression of synaptic cell-adhesion molecules overlaps with other key features of cellular identity and diversity.

From tonsils to scopes: 80 years of variation in the practice of otolaryngology.

Variation in medicine and surgery is a critical contemporary health policy issue. Recent research demonstrates that variation in Medicare payments to otolaryngologists in a single metropolitan area was attributable to differences in health care resource utilization among physicians and that the hospital with the highest Medicare payments per physician had a higher proportion of office endoscopy-related relative value units than that of other providers, relying less on evaluation and management office visits for revenue. This study is the latest in a line of fascinating case records of variation in otolaryngology and other surgical specialties dating back to the work of J. Alison Glover in 1938.

Risk of corticosteroid-related adverse events in asthma patients with high oral corticosteroid use.

BACKGROUND: Oral corticosteroids (OCS) are a mainstay of asthma treatment. Their use increases the risk of various corticosteroid-related adverse events, but the extent of risk is poorly characterized. OBJECTIVE: To determine the incremental risk of possible corticosteroid-related adverse events (AE) in asthma among patients with high OCS use compared with patients who do not use OCS. METHODS: Patients with asthma in a commercial health care claims data base who were high-OCS users (≥30 days of OCS use annually) were matched to no-OCS users by age, sex, and geographic region, and the presence or absence of chronic obstructive pulmonary disease (COPD) as a comorbidity. We examined bone-related conditions, pneumonia, opportunistic infections, diabetes mellitus, and other disorders as potential AEs by using χ(2) tests to compare potential AE prevalence between the cohorts, with and without stratification by a COPD diagnosis. We controlled for the number of inhaled steroids (ICS) canisters filled. RESULTS: A total of 3604 patients with asthma and high OCS use were matched to 3604 patients who did not use OCS (mean age, 54.4; 68.1% female; 44.9% with COPD). Patients with high OCS use had statistically significantly higher rates of any potential AE compared with patients who did not use OCS (83.5% versus 78.1%), (p < 0.001). Rates of individual potential AEs were also higher in patients who used higher doses of OCS. Patterns of AEs were similar in patients with and those without COPD, with statistically significantly higher overall AE risk and individual risks in high-OCS users. The number of ICS canisters filled was not a significant predictor of AE. CONCLUSION: Patients with asthma who were treated with OCS for ≥30 days per year have a greater overall risk of possible corticosteroid-related AEs compared with those patients with no OCS use, whether or not they had COPD.

Treatment patterns in Cushing's disease patients in two large United States nationwide databases: application of a novel, graphical methodology.

PURPOSE: Data on real-world treatment patterns for Cushing's disease (CD) are limited. We used a novel graphical technique to analyze treatment patterns in CD patients in the United States. METHODS: Two combined US claims databases were used to identify CD patients with claims with Cushing's syndrome diagnosis and either benign pituitary adenoma or hypophysectomy and newly-treated in 2008 (no treatment in prior 6 months). Patients were followed from first treatment day until end of enrollment or 12/31/2010. We compared summary statistics with a novel graphical methodology that simultaneously displays individual color-coded patient treatment histories. RESULTS: Among 228 newly-treated CD patients, 180 (78.9%) had surgery as first observed treatment, 42 (18.4%) had pharmacotherapy, and 6 (2.6%) had radiotherapy. In 42 patients who had pharmacotherapy as first treatment, dopamine agonists were used as first pharmacotherapy in 24 (57.1%), ketoconazole in 17 (40.5%), and mitotane in one patient (2.4%). In 180 patients with surgery as first treatment, 15 (8.3%) later had radiotherapy and 14 (7.8%) had pharmacotherapy. In 42 patients who had pharmacotherapy as first treatment, 10 (23.8%) later had surgery and 2 (4.8%) had radiotherapy. Mean duration of first pharmacotherapy varied: 369.5 days for dopamine agonists, 157.1 for ketoconazole, and 30.0 for mitotane. CONCLUSIONS: This study addresses a need for US data on real-world treatment patterns for CD patients. The majority of CD patients undergo surgery as initial therapy. Patients using pharmacotherapy had limited persistence with treatment. Neither reasons for discontinuation of therapy nor the impact of a recent FDA warning on potentially fatal liver toxicity from ketoconazole could be assessed.

Clinical practice guideline: tinnitus.

OBJECTIVE: Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient's quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. PURPOSE: The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. ACTION STATEMENTS: The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (≥ 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (≥ 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); and (b) recommend sound therapy to patients with persistent, bothersome tinnitus. The development group provided no recommendation regarding the effect of acupuncture in patients with persistent, bothersome tinnitus.