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.

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.

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.

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.

Association between hospital case volume and the use of bronchoscopy and esophagoscopy during head and neck cancer diagnostic evaluation.

BACKGROUND: There are no clinical guidelines on best practices for the use of bronchoscopy and esophagoscopy in diagnosing head and neck cancer. This retrospective cohort study examined variation in the use of bronchoscopy and esophagoscopy across hospitals in Michigan. METHODS: A total of 17,828 patients were identified with head and neck cancer in the 2006 to 2010 Michigan State Ambulatory Surgery Databases. A hierarchical, mixed-effect logistic regression was used to examine whether a hospital's risk-adjusted rate of concurrent bronchoscopy or esophagoscopy was associated with its case volume (< 100, 100-999, or ≥ 1000 cases per hospital) for those undergoing diagnostic laryngoscopy. RESULTS: Of 9218 patients undergoing diagnostic laryngoscopy, 1191 (12.9%) received concurrent bronchoscopy and 1675 (18.2%) underwent concurrent esophagoscopy. The median hospital rate of bronchoscopy was 2.7% (range, 0%-61.1%), and low-volume (odds ratio [OR] = 27.1; 95% confidence interval [CI] = 1.9, 390.7) and medium-volume (OR = 28.1; 95% CI = 2.0, 399.0) hospitals were more likely to perform concurrent bronchoscopy compared to high-volume hospitals. The median hospital rate of esophagoscopy was 5.1% (range, 0%-47.1%), and low-volume (OR = 9.8; 95% CI = 1.5, 63.7) and medium-volume (OR = 8.5; 95% CI = 1.3, 55.0) hospitals were significantly more likely to perform concurrent esophagoscopy relative to high-volume hospitals. CONCLUSIONS: Patients with head and neck cancer who are undergoing diagnostic laryngoscopy are much more likely to undergo concurrent bronchoscopy and esophagoscopy at low- and medium-volume hospitals than at high-volume hospitals. Whether this represents overuse of concurrent procedures or appropriate care that leads to earlier diagnosis and better outcomes merits further investigation.

The effect of pre-Affordable Care Act (ACA) Medicaid eligibility expansion in New York State on access to specialty surgical care.

BACKGROUND: Critics argue that expanding health insurance coverage through Medicaid may not result in improved access to care. The Affordable Care Act provides reimbursement incentives aimed at improving access to primary care services for new Medicaid beneficiaries; however, there are no such incentives for specialty services. Using the natural experiment of Medicaid expansion in New York (NY) State in October 2001, we examined whether Medicaid expansion increased access to common musculoskeletal procedures for Medicaid beneficiaries. METHODS: From the State Inpatient Database for NY State, we identified 19- to 64-year-old patients who underwent lower extremity large joint replacement, spine procedures, and upper/lower extremity fracture/dislocation repair from January 1998 to December 2006. We used interrupted time series analysis to evaluate the association between Medicaid expansion and trends in the relative and absolute number of Medicaid beneficiaries who underwent these musculoskeletal procedures. RESULTS: Before Medicaid expansion, we observed a slight but steady temporal decline in the proportion of musculoskeletal surgical patients who were Medicaid beneficiaries. After expansion, this trend reversed, and by 5 years after Medicaid expansion, the proportion of musculoskeletal surgical patients who were Medicaid beneficiaries was 4.7 percentage points [95% confidence interval, 3.9-5.5] higher than expected, based on the preexpansion time trend. CONCLUSION: Medicaid expansion in NY State significantly improved access to common musculoskeletal procedures for Medicaid beneficiaries.

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.

Prospective head and neck cancer research: a four-decade bibliometric perspective.

BACKGROUND: It is unknown whether changes in study sponsorship have affected the proportion of prospective research on surgery, radiotherapy, and pharmacotherapy for head and neck squamous cell carcinoma (HNSCC) being published over time. PATIENTS AND METHODS: We examined prospective studies from PubMed, Ovid MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1980, 1985, 1990, 1995, 2000, 2005, and 2010. Chi-squared tests were used to identify significant associations between sponsorship and authorship, treatments within study protocols, and presentation of results, whereas time-based trends were analyzed using the Cochran-Armitage test. RESULTS: Among 309 articles, industry (70, 22.7%) and the U.S. government (65, 21%) were the most common sponsors. There was a significant increase in the proportion of industry-sponsored research (p for trend = .013) and a decline in U.S. government-sponsored research (p for trend = .001) over time. The inclusion of surgery in treatment protocols declined over the past four decades (p for trend = .003). Protocols incorporating pharmacotherapy were more likely to have industry support than those without pharmacotherapy (p = .001), whereas protocols with radiotherapy (p = .003) or surgery (p = .002) were less likely to have industry support. CONCLUSION: Industry is the predominant sponsor of prospective HNSCC research, with an emphasis on pharmacotherapy.

Variation in inpatient tonsillectomy costs within and between US hospitals attributable to postoperative complications.

BACKGROUND: Tonsillectomy is the second most common inpatient procedure in US children. However, the factors that influence tonsillectomy-related costs are unknown. OBJECTIVE: The objective of the study was to describe variation in US inpatient tonsillectomy costs and examine whether postoperative complications contribute to these disparities in costs. RESEARCH DESIGN: This is a retrospective cohort study of the 2009 Nationwide Inpatient Sample. Hierarchical, mixed-effects linear regression modeling was used to analyze the association between postoperative complications and cost, controlling for clinically relevant characteristics such as age, number of chronic comorbidity indicators, and hospital mean complication rates. We also estimated the variance in cost attributable to the treating hospital using the intraclass correlation coefficient. SUBJECTS: The study cohort comprised 12,512 adult and pediatric patients undergoing tonsillectomy or adenotonsillectomy in the inpatient setting. MEASURES: Cost, posttonsillectomy hemorrhage, and mechanical ventilator use at the individual encounter and at hospital level were evaluated. RESULTS: The aggregate cost of tonsillectomies in the cohort was $94.2 million. The median cost per encounter across all hospitals was $4393 (interquartile range, $3279-$6981), whereas the mean cost was $7525 (95% confidence interval, $6453-$8597). Mechanical ventilation was associated with an adjusted increase of $30,081 per encounter (95% confidence interval, $18,199-$41,964). The intraclass correlation coefficient declined from 0.117 to 0.070 after adjusting for mean hospital mechanical ventilation rate, which accounted for 40.2% of the interhospital variation in cost. CONCLUSIONS: Use of mechanical ventilation significantly increases the cost of inpatient tonsillectomy care. Further research should examine risk factors contributing to higher rates of mechanical ventilation after tonsillectomy, which in turn can guide systemic quality improvement interventions to reduce costs.

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.

Inpatients with gunshot wounds to the face.

Microvascular free tissue transfer (FTT) is an increasingly used method of reconstruction for traumatic defects of the head and neck. We describe the immediate management, FTT reconstruction techniques, and outcomes of 6 individuals who sustained maxillofacial gunshot trauma and were treated at a single tertiary-care level I trauma center. All 6 patients were white men with a mean age of 33 years. The mandible, nose, and orbital contents were the most frequently affected critical structures. All patients initially underwent primary wound debridement and tracheostomy, with concurrent maxillomandibular wire fixation and/or midface or mandible plate fixation in 5 patients. The mean time from injury to definitive FTT was 38 days. Five patients underwent fibula osteocutaneous FTT and 1 underwent radial forearm fasciocutaneous FTT. One patient also underwent concurrent local tissue rearrangement and pedicled flap surgery for nasal reconstruction. The mean hospital length of stay after FTT was 6 days. All FTT survived without necrosis. Oral incompetence and poor cosmesis from undesirable scarring patterns were the most common long-term complications. In summary, successful reconstruction of head and neck defects caused by gunshot trauma begins with airway stabilization, wound management, and bony fracture reduction and fixation. Definitive microvascular FTT is a useful method of repairing traumatic head and neck defects, although long-term functional and cosmetic complications may still occur.

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.

Use of the average baseline versus the time-matched baseline in parallel group thorough QT/QTc studies.

Using historical studies, we compared the impact of using the average baseline or time-matched baseline on diurnal effect correction, treatment effect estimation, and analysis of variance/covariance (ANOVA/ANCOVA) efficiency in a parallel thorough QT/QTc (TQT) study. Under a multivariate normal distribution assumption, we derived conditions for achieving unbiasness and better efficiency when using the average baseline, and confirmed these conditions using historical TQT studies. Furthermore, simulations were conducted under the randomized trial with and without observed imbalanced baseline settings. We conclude that the analyses using average baseline yield better efficiency and unbiased or less biased results under our TQT study conditions.

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.

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.

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.