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Background Medically refractory chronic rhinosinusitis (CRS) is often treated with functional endoscopic sinus surgery (FESS) and high-volume steroid nasal irrigation. While budesonide is the most common steroid irrigation for this indication, mometasone has a superior pharmacokinetic profile, which may allow dose escalation. The safety and efficacy of mometasone at higher concentrations than previously used in treating CRS have not been explored. Methods Patients were recruited from a tertiary level clinic between June 2018 and December 2019. Inclusion criteria included adults (>18 years); CRS diagnosis; previous FESS; pre-treatment morning cortisol within normal range; minimum of twice daily high-volume sinonasal mometasone irrigations (total dose of 4 mg) for 12 weeks; and post-treatment morning cortisol measured within 2 weeks following the study period. Patients with potential for endogenous or exogenous disruption of the HPA axis were excluded. Results 14 patients were enrolled in this prospective cohort study. In all but one patient, pre- and post-treatment morning cortisol levels were not significantly different and were within normal limits (6.7-25.4 μg/dL). Following an uninterrupted 12-week treatment course, no evidence of HPA axis suppression was found (P = 0.915). The single patient who was found to have a low (1.3 μg/dL) post-treatment morning serum cortisol level reportedly received an intraarticular steroid shot several days prior to the blood draw. She remained asymptomatic and her rechecked serum cortisol was within normal limits at 12.3 μg/dL. Conclusions High-volume 2 mg twice daily sinonasal mometasone irrigations did not cause HPA axis suppression in a representative sample of patients with refractory CRS post-FESS with normal baseline cortisol levels.

Tubulin superfamily (TSF) proteins are widespread, and are known for their multifaceted roles as cytoskeletal proteins underpinning many basic cellular functions, including morphogenesis, division, and motility. In eukaryotes, tubulin assembles into microtubules, a major component of the dynamic cytoskeletal network of fibres, whereas the bacterial homolog FtsZ assembles the division ring at midcell. The functions of the lesser-known archaeal TSF proteins are beginning to be identified and show surprising diversity, including homologs of tubulin and FtsZ as well as a third archaea-specific family, CetZ, implicated in the regulation of cell shape and possibly other unknown functions. In this study, we define sequence and structural characteristics of the CetZ family and CetZ1 and CetZ2 subfamilies, identify CetZ groups and diversity amongst archaea, and identify potential functional relationships through analysis of the genomic neighbourhoods of cetZ genes. We identified at least three subfamilies of orthologous CetZ proteins in the archaeal class Halobacteria, including CetZ1 and CetZ2 as well as a novel uncharacterized subfamily. CetZ1 and CetZ2 were correlated to one another as well as to cell shape and motility phenotypes across diverse Halobacteria. Among other known CetZ clusters in orders Archaeoglobales, Methanomicrobiales, Methanosarcinales, and Thermococcales, an additional uncharacterized group from Archaeoglobales and Methanomicrobiales is affiliated strongly with Halobacteria CetZs, suggesting that they originated via horizontal transfer. Subgroups of Halobacteria CetZ2 and Thermococcales CetZ genes were found adjacent to different type IV pili regulons, suggesting potential utilization of CetZs by type IV systems. More broadly conserved cetZ gene neighbourhoods include nucleotide and cofactor biosynthesis (e.g., F420) and predicted cell surface sugar epimerase genes. These findings imply that CetZ subfamilies are involved in multiple functions linked to the cell surface, biosynthesis, and motility.

Background: Sinusitis complicated by intracranial or orbital extension can be life-threatening and require emergent intervention. Histologic features of complicated sinusitis have yet to be determined and may have significant implications for understanding pathophysiology. Methods: A structured histopathology report was utilized to analyze sinus tissue extracted during functional endoscopic sinus surgery (FESS). A total of 13 histopathology variables were compared between patients with complicated sinusitis (CS), CRS without nasal polyps (CRSsNP), and CRS with nasal polyps (CRSwNP). Results: About 24 CS, 149 uncomplicated CRSsNP, and 191 uncomplicated CRSwNP patients were analyzed. Nasal tissue from CS and CRSwNP patients demonstrated similar levels of overall inflammation (66.7% vs. 69.6% with moderate/severe inflammation, P = .466). Relative to CRSsNP, CS patients showed significantly greater overall inflammation (66.7% vs. 41.6%, P = .019). CS patients demonstrated significantly fewer eosinophils per high power field (eos/HPF) and eosinophil aggregates compared to CRSwNP patients (20.8% vs. 70.7% with 5+eos/HPF, P Conclusion: Significant histopathological differences were evident in patients with CS, CRSsNP, and CRSwNP. CS patients did not perfectly fit either a CRSsNP or CRSwNP profile, underscoring the importance of delineating the histopathological features of CS. This study offers insight into the histologic aspects of CS, providing initial evidence that it is an aggressive neutrophilic inflammatory process.

OBJECTIVES To assess patient acceptance of resident involvement in otolaryngologic procedures and to evaluate the impact of a written preoperative educational pamphlet. STUDY DESIGN Prospective cohort study. METHODS This is a prospective survey study at a large tertiary care academic center. In addition to standard perioperative instructions and informed consent, 87 out of 183 patients received a pamphlet with information on the role of the otolaryngology resident. RESULTS Greater than 90% of all patients surveyed recognized that resident physicians are directly involved in delivering care at teaching hospitals and may have assisted in their surgical procedure. Ninety percent of patients receiving educational pamphlets were aware residents may have performed portions of their procedure versus 71% in the control group (P = .001). Ninety-seven percent of patients receiving pamphlets wanted to know how much of their procedure was performed by a resident versus 71% of the control group (P

Background Ambient air pollution is well known to cause inflammatory change in respiratory epithelium and is associated with exacerbations of inflammatory conditions such as asthma and chronic obstructive pulmonary disease. However, limited work has been done on the impact of air pollution on pathogenesis of chronic rhinosinusitis and there are no reports in the literature of how pollutant exposure may impact sinonasal histopathology in patients with chronic rhinosinusitis. Objective This study aims to identify associations between certain histopathologic characteristics seen in sinus tissue of patients with chronic rhinosinusitis (CRS) and levels of particulate air pollution (PM2.5) and ground-level ozone in their place of residence. Methods A structured histopathology report was created to characterize the tissues of CRS patients undergoing sinus surgery. An estimate for each patient’s exposure to air pollutants including small particulate matter (PM2.5) and ground-level ozone was obtained using the Environmental Protection Agency’s (EPA) Environmental Justice Screening and Mapping Tool (EJSCREEN). Mean pollutant exposures for patients whose tissues exhibited varying histopathologic features were compared using logistic regression models. Results Data from 291 CRS patients were analyzed. Higher degree of inflammation was significantly associated with increased ozone exposure (p = 0.031). Amongst the patients with CRSwNP (n=131), presence of eosinophilic aggregates (p = 0.018) and Charcot-Leyden crystals (p = 0.036) was associated with increased ozone exposure. Conclusion Exposure to ambient air pollutants may contribute to pathogenesis of CRS. Increasing ozone exposure was linked to both higher tissue inflammation and presence of eosinophilic aggregates and Charcot-Leyden crystals in CRSwNP patients.

Background: Structured histopathology reporting is increasingly being utilized in rhinology to characterize endotypes in chronic rhinosinusitis and guide management decisions after sinus surgery. Objective: The goal of this investigation is to evaluate inter-observer agreement in structured histopathology reporting. Methods: Two experienced head and neck pathologists independently compiled structured histopathology reports for tissue samples collected during functional endoscopic sinus surgery. Cohen’s standard kappa (κ) coefficients were calculated for each histopathologic variable to assess inter-pathologist agreement. Results: A total of 92 cases were analyzed. Substantial inter-pathologist agreement was reached on tissue eosinophil count (κ = 0.64, P Conclusion: High inter-pathologist agreement was demonstrated for several salient histopathologic variables, including tissue eosinophil count and the presence of eosinophil aggregates. However, refining the definitions of certain histopathologic variables may improve the reproducibility of structured histopathology reporting.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent, ubiquitous pollutants. It is important to continuously monitor the presence of PFAS contamination, utilizing both legacy and new sentinels. In this study, environmental PFAS levels were evaluated using ticks as a sentinel model due to their world-wide distribution, hematophagous nature, and ease of collection and sampling. Hematophagy in discrete blood meals, from a suite of vertebrates, allows ticks to sample dozens of species of consumers and bioaccumulation across communities. Four different species of ticks, across two states (NY, n = 28 in mid-April of 2020 and FL, n = 32 between 2015 and 2020) with two sampling sites in each state were analyzed for the presence of 53 PFAS. The total PFAS concentration in ticks was the lowest at Newburgh (NY), a site that has been undergoing remediation efforts, while the highest total PFAS concentrations were measured in ticks at the Sweetwater site, a wastewater treatment wetland. Detection of PFAS and the potential for variation between tick species and between locations are necessary to establish the utility of ticks as sentinels, in addition to assessing additional environmental factors, such as other wildlife, water, or soil.

Background Smoking status has been established as a known irritant of the upper and lower respiratory tracts, leading to inflammation throughout the respiratory system. Tobacco smoking is one comorbidity encountered among chronic rhinosinusitis (CRS) patients. The histopathologic features of CRS and comorbid smoking status have yet to be determined by structured histopathology and may have important implications on disease management. Methods Retrospective study of structured histopathology reports analyzing sinus tissue removed during functional endoscopic sinus surgery. Histopathology variables were compared among patients with CRS who were reported as never smokers, former smokers, or current smokers. Results A total of 285 CRS patients were included: 173 never smokers, 85 former smokers, and 27 current smokers. When compared with former smokers, current smokers demonstrated increased basement membrane thickening (88.9% vs 67.1%, P Conclusion Smoking status may influence histopathologic tissue-level changes in CRS disease. Interestingly, former and current smokers maintained few differences in histopathology. However, former and current smokers collectively demonstrated increased chronic inflammatory changes compared with never smokers. These findings suggest that the timing of smoking exposure has limited effect on the tissue level, rather exposure overall influences inflammatory change. These findings may have important implications on medical and surgical management of CRS disease and comorbid smoking status.

As evidence-based medicine has taken hold across medical specialties, the level of evidence within the facial plastic surgery literature has risen, but remains weak in comparison. There has not yet been a systematic, critical appraisal of the relative strength of evidence among subsets of the practice of facial plastic surgery. The current study is a systematic review, designed to evaluate the level of evidence observed in the facial plastic surgery literature. Five journals were queried using facial plastic surgery terms for four selected years over a 10-year period. Following screening, articles were assigned to a category regarding subject matter, assessed for the presence of various methodological traits, and evaluated for overall level of evidence. Comparisons were made in regard to level of evidence across the breadth of facial plastic surgery subject matter. A total of 826 articles were included for final review. Studies on operative facial rejuvenation and rhinoplasty had significantly fewer authors on average than studies on cancer reconstruction or craniofacial topics. Craniofacial studies demonstrated higher levels of evidence relative to all other categories, with the exception of facial paralysis and facial trauma studies, from which there was no significant difference. In general, reconstructive studies had significantly more authors and higher levels of evidence than did articles with an aesthetic focus. Level of evidence in facial plastic surgery remains relatively weak overall. Reconstructive and particularly craniofacial studies demonstrate higher mean level of evidence, relative to other subsets of facial plastic surgery. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266

Background: Knowledge of the quality of evidence in facial plastic surgery research is essential for the implementation of evidence-based practices. The purpose of this study is to provide an updat...

Adult and pediatric patients with chronic rhinosinusitis (CRS) may have differing philosophies in therapeutic management. Few studies have examined sinonasal tissue-level comparisons of these groups. This study examines histopathologic differences between children and adults with CRS, with the goal of understanding disease pathogenesis and optimizing medical management for both populations.In a retrospective cohort of CRS patients who underwent functional endoscopic sinus surgery (FESS), demographic factors, pertinent comorbidities, and a structured histopathologic report of 13 variables were compared across pediatric and adult CRS patients with and without nasal polyps (pCRSwNP, pCRSsNP, aCRSwNP, aCRSsNP, respectively).A total of 378 adult (181 aCRSsNP, 197 aCRSwNP) and 50 pediatric (28 pCRSsNP, 22 pCRSwNP) patients were analyzed. Significantly more children compared with adults had a comorbid asthma diagnosis (64.5% vs. 37.2%, p = 0.003). Adults with CRS exhibited significantly more tissue neutrophilia (28.9% vs. 12.0%, p = 0.006), basement membrane thickening (70.3% vs. 44.0%, p 0.001), subepithelial edema (61% vs. 30.0%, p 0.001), squamous metaplasia (22.0% vs. 4.0%, p 0.001), and eosinophil aggregates (22.8% vs. 4.0%, p 0.001) than children with CRS. The majority (66.5%) of adult CRS patients exhibited a lymphoplasmacytic-predominant inflammatory background, whereas the majority (57.8%) of children with CRS exhibited a lymphocyte-predominant inflammatory background.Sinonasal tissue of adult and pediatric CRS patients demonstrates clear histopathologic differences. Our findings provide insight into differing pathophysiology, which may enable optimization of targeted therapies for patients in each of these unique clinical groups.

Background Adult and elderly patients with chronic rhinosinusitis (CRS) undergo similar therapeutic management. Few studies have undertaken sinonasal tissue-level comparisons of these groups. This study examines histopathological differences between adults (>18, Methods In a retrospective cohort analysis, demographic factors, comorbidities, and a structured histopathological report of 13 variables were compared across adult and elderly patients with CRS who underwent functional endoscopic sinus surgery. These cohorts of adult and elderly patients included patients with and without nasal polyps (NP). Results Three hundred adult (158 aCRSsNP, 142 aCRSwNP) and 77 elderly (38 eCRSsNP, 39 eCRSwNP) patients were analyzed. Mean age of the adult cohort was 44.4 ± 12.4 years, while that of the elderly cohort was 71.9 ± 5.9 years ( P Conclusion Sinonasal tissue of adult and elderly patients with CRS demonstrates clear histopathological differences. Patient comorbidities, in addition to histopathological characterizations, may provide further context for management optimization. Level of Evidence 2. Short Summary Sinonasal tissue samples from adult and elderly patients with CRS demonstrate clear histopathological differences. These patient populations also exhibit unique comorbidities. These distinctions have the potential to inform and optimize management of this condition.

Background A subset of chronic rhinosinusitis (CRS) patients demonstrates tissue eosinophilia on structured histopathology. Prior studies have suggested that these patients are at increased risk for recurrent disease. The goals of this study are to identify histopathologic features of CRS patients with tissue eosinophilia and compare the influence of tissue eosinophilia to the effects of age and revision surgery on histopathology. Methods A structured histopathology report was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery. Binomial logistic regression analysis was conducted to evaluate the association of age at diagnosis, tissue eosinophil count, and history of revision surgery with histopathology variables. Results A total of 281 CRS patients were included, of which 106 had tissue eosinophilia. Regression analysis demonstrated that tissue eosinophilia was associated with degree of inflammation (odds ratio [OR] 5.744; P < .001), neutrophilic infiltrate (OR 1.882; P = .020), basement membrane thickening (OR 3.561; P < .001), squamous metaplasia (OR 3.315; P < .001), fibrosis (OR 2.246; P = .002), presence of Charcot–Leyden crystals (OR 20.700; P = .004), and eosinophilic aggregates (OR 34.172; P < .001). Age and history of revision surgery were not significant predictors of histopathology variables on multivariate analysis. Conclusion Tissue eosinophilia appears to be the predominant driving factor of histopathologic changes irrespective of previous sinus surgery or age at diagnosis. These findings may have important implications for postsurgical management and prognosis for patients with tissue eosinophilia presenting for revision surgery.

Studies of patients afflicted by neurodegenerative diseases suggest that misfolded proteins spread through the brain along anatomically connected networks, prompting progressive decline. Recently, mouse models have recapitulated the cell-to-cell transmission of pathogenic proteins and neuron death observed in patients. However, the factors regulating the spread of pathogenic proteins remain a matter of debate due to an incomplete understanding of how vulnerability functions in the context of spread. Here we use quantitative pathology mapping in the mouse brain, combined with network modeling to understand the spatiotemporal pattern of spread. Patterns of α-synuclein pathology are well described by a network model that is based on two factors: anatomical connectivity and endogenous α-synuclein expression. The map and model allow the assessment of selective vulnerability to α-synuclein pathology development and neuron death. Finally, we use quantitative pathology to understand how the G2019S LRRK2 genetic risk factor affects the spread and toxicity of α-synuclein pathology.

Objectives/hypothesis This study offers an update on the epidemiologic and prognostic factors and treatment-specific outcomes in patients diagnosed with sinonasal diffuse large B-cell lymphoma (DLBCL). Study design Retrospective cohort study. Methods National Cancer Database was queried from 2004 to 2016 for patients with sinonasal DLBCL. Univariate Kaplan-Meier and multivariate Cox-regression analyses were performed to evaluate the association of suspected prognostic factors with overall survival (OS). Results A total of 2,222 patients with sinonasal DLBCL were analyzed. OS was 62% at 5 years and 42% at 10 years. Prognostic factors associated with increased survival included African-American race (HR: 0.48, 95% CI: 0.33-0.70), chemotherapy (HR: 0.30, CI: 0.25-0.35), and radiation (HR: 0.80, CI: 0.69-0.93). Prognostic factors associated with decreased survival included patients with Charlson-Deyo scores of 1 (HR: 1.51, CI: 1.25-1.84), 2 (HR: 2.25, CI: 1.67-3.03), and 3 (HR: 2.36, CI: 1.49-3.74) and patients with Lugano stage III (HR: 1.69, CI: 1.09-2.62) and IV (HR: 1.96, CI: 1.46-2.64) disease. Stage-based split multivariate analysis was performed and revealed chemotherapy was independently associated with increased OS in patients with stage I (HR: 0.24, CI: 0.19-0.30), II (HR: 0.17, CI: 0.11-0.28), and IV (HR: 0.41, CI: 0.26-0.64) disease. Radiotherapy was independently associated with increased OS in patients with stage I disease only (HR: 0.67, CI: 0.55-0.83), while immunotherapy was an independent prognostic factor in patients with stage IV disease only (HR: 0.60, CI: 0.37-0.98). Conclusion This study is the largest to date to analyze the association of demographic features and treatment modalities with OS in patients with sinonasal DLBCL. It is the first to investigate the association of immunotherapy with OS in this population. A combination treatment of immunochemotherapy or radioimmunochemotherapy confers increased survival, particularly in patients with advanced disease. Level of evidence IV Laryngoscope, 2021.

Spread of tau pathology follows brain connectivity, is modulated by selective vulnerability, and is predicted by network analysis., Neuropathological staging studies have suggested that tau pathology spreads through the brain in Alzheimer’s disease (AD) and other tauopathies, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute. In this study, we seed tau pathology in the brains of nontransgenic mice with AD tau and quantify pathology development over 9 months in 134 brain regions. Network modeling of pathology progression shows that diffusion through the connectome is the best predictor of tau pathology patterns. Further, deviations from pure neuroanatomical spread are used to estimate regional vulnerability to tau pathology and identify related gene expression patterns. Last, we show that pathology spread is altered in mice harboring a mutation in leucine-rich repeat kinase 2. While tau pathology spread is still constrained by anatomical connectivity in these mice, it spreads preferentially in a retrograde direction. This study provides a framework for understanding neuropathological progression in tauopathies.

Some microbes display pleomorphism, showing variable cell shapes in a single culture, whereas others differentiate to adapt to changed environmental conditions. The pleomorphic archaeon Haloferax volcanii commonly forms discoid-shaped (‘plate’) cells in culture, but may also be present as rods, and can develop into motile rods in soft agar, or longer filaments in certain biofilms. Here we report improvement of H. volcanii growth in both semi-defined and complex media by supplementing with eight trace element micronutrients. With these supplemented media, transient development of plate cells into uniformly shaped rods was clearly observed during the early log phase of growth; cells then reverted to plates for the late log and stationary phases. In media prepared with high-purity water and reagents, without supplemental trace elements, rods and other complex elongated morphologies (‘pleomorphic rods’) were observed at all growth stages of the culture; the highly elongated cells sometimes displayed a substantial tubule at one or less frequently both poles, as well as unusual tapered and highly curved forms. Polar tubules were observed forming by initial mid-cell narrowing or tubulation, causing a dumbbell-like shape, followed by cell division towards one end. Formation of the uniform early log-phase rods, as well as the pleomorphic rods and tubules were dependent on the function of the tubulin-like cytoskeletal protein, CetZ1. Our results reveal the remarkable morphological plasticity of H. volcanii cells in response to multiple culture conditions, and should facilitate the use of this species in further studies of archaeal biology.

BACKGROUND: Atopy has a strong association with chronic rhinosinusitis (CRS). OBJECTIVE: To understand whether patients with atopy and CRS can be defined by markers of tissue histopathology, systemic biomarkers, and clinical factors, that may guide their response to new pharmacologic agents. METHODS: In a retrospective cohort of CRS patients who underwent functional endoscopic sinus surgery (FESS), a structured histopathology report consisting of 12 variables, comorbid conditions, preoperative total serum IgE levels, and preoperative modified Lund-Kennedy (LK) endoscopic and Sinonasal outcome test (SNOT-22) scores were compared between aCRS and non-aCRS control patients in a multivariable model. RESULTS: 380 CRS patients were enrolled. 286 had comorbid atopy (aCRS). Compared to non-aCRS, aCRS patients had significantly higher preoperative total SNOT-22 scores (40.45±22.68 vs. 29.70±20.68, P=0.015) and symptom-specific SNOT-22 scores in all domains except psychological dysfunction. Relative to non-aCRS, aCRS patients had: increased tissue eosinophilia (P

Bassil et al. model the crosstalk of α-syn and tau under copathology conditions. They show evidence of α-syn–dependent tau pathology in the human brain. Moreover, they demonstrate the role of α-syn in the modulation of tau pathology in mice., α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate–derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

Tau pathology is a diagnostic feature of Alzheimer’s disease (AD) but is also a prominent feature of Parkinson’s disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathology’s initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.

Alpha-synuclein (aSyn) participates in synaptic vesicle trafficking and synaptic transmission, but its misfolding is also strongly implicated in Parkinson’s disease (PD) and other neurodegenerative disorders known as synucleinopathies where misfolded aSyn accumulates in different regions of the central and peripheral nervous systems. Although increased aSyn expression levels or altered aggregation propensities likely underlie familial PD with SNCA amplification or mutations, the majority of synucleinopathies arise sporadically, indicating that disease can develop under normal levels of wildtype aSyn. We report here the development and characterization of a mouse line expressing an aSyn-GFP fusion protein under the control of native Snca regulatory elements. Regional and subcellular localization of the aSyn-GFP fusion protein in brains and peripheral tissues of knock-in (KI) mice are indistinguishable from that of wildtype littermates. Importantly, similar to wildtype aSyn, aSyn-GFP disperses from synaptic vesicles upon membrane depolarization, indicating that the tag does not alter normal aSyn dynamics at synapses. In addition, intracerebral injection of aSyn pre-formed fibrils into KI mice induced the formation of aSyn-GFP inclusions with a distribution pattern similar to that observed in wildtype mice, albeit with attenuated kinetics due to the GFP tag. We anticipate that this new mouse model will facilitate in vitro and in vivo studies requiring in situ detection of endogenous aSyn, therefore providing new insights into aSyn function in health and disease.Significance StatementAlpha-synuclein (aSyn) participates in synaptic vesicle function and represents a major component of the Lewy pathology found in Parkinson’s and related neurodegenerative diseases. The function of aSyn and the sequence of events leading to its aggregation and neurotoxicity are not fully understood. Here we present a new mouse model in which Enhanced Green Fluorescence Protein (GFP) has been knocked-in at the C-terminal of the Snca gene. The resulting fusion protein shows identical expression and localization to that of wildtype animals, is functional, and is incorporated into pathological aggregates in vitro and in vivo. This new tool allows for monitoring aSyn under a variety of physiological and pathological conditions, and may uncover additional insights into its function and dysfunction.

Objective:This study explored the impact of laryngopharyngeal reflux (LPR) on quality-of-life outcomes captured by Sino-Nasal Outcome Test (SNOT-22) and Reflux Symptom Index (RSI) in patients with chronic rhinosinusitis (CRS) and patients with symptoms of LPR.Methods:In a retrospective chart review, SNOT-22 and RSI scores were analyzed in patients seen at a tertiary care center with CRS, LPR, or both CRS and LPR. SNOT-22 items were grouped into sleep, nasal, otologic, and emotional symptom subdomains.Results:A total of 138 patients (36 with CRS alone, 60 with LPR alone, and 42 with both CRS and LPR) were included. Compared to patients with CRS alone, those with CRS and LPR (CRS+LPR) had higher SNOT-22 total (50.54 ± 19.53 vs 35.31 ± 20.20, P < .001), sleep (19.61 ± 9.31 vs 14.42 ± 10.34, P < .022), nasal (17.38 ± 7.49 vs 11.11 ± 8.52, P < .001), otologic subdomains (9.17 ± 5.07 vs 5.53 ± 5.14, P < .002), and RSI (22.06 ± 9.42 vs 10.75 ± 8.43, P < .003). Patients with LPR alone had higher RSI compared to those with CRS (18.48 ± 9.77 vs 10.75 ± 8.43, P < .037). RSI and SNOT-22 scores were positively correlated irrespective of patient group (R = 0.289, P = .003).Conclusion:Compared to patients with CRS or LPR alone, those with CRS+LPR demonstrated higher RSI and total and subdomain SNOT-22 scores. Patients with LPR alone had elevated SNOT-22 despite absent endoscopic evidence of sinusitis.

Some microbes display pleomorphism, showing variable cell shapes in a single culture, whereas others differentiate to adapt to changed environmental conditions. The pleomorphic archaeon Haloferax volcanii commonly forms discoid-shaped (‘plate’) cells in culture, but may also be present as rods, and can develop into motile rods in soft agar, or longer filaments in certain biofilms. Here we report improvement of H. volcanii growth in both semi-defined and complex media by supplementing with eight trace element micronutrients. With these supplemented media, transient development of plate cells into uniformly shaped rods was clearly observed during the early log phase of growth; cells then reverted to plates for the late log and stationary phases. In media prepared with high-purity water and reagents, without supplemental trace elements, rods and other complex elongated morphologies (‘pleomorphic rods’) were observed at all growth stages of the culture; the highly elongated cells sometimes displayed a substantial tubule at one or less frequently both poles, as well as unusual tapered and highly curved forms. Polar tubules were observed forming by initial mid-cell narrowing or tubulation, causing a dumbbell-like shape, followed by cell division towards one end. Formation of the uniform early log-phase rods, as well as the pleomorphic rods and tubules were dependent on the function of the tubulin-like cytoskeletal protein, CetZ1. Our results reveal the remarkable morphological plasticity of H. volcanii cells in response to multiple culture conditions, and should facilitate the use of this species in further studies of archaeal biology.

Core Buddhist principles of continuity, karmic assignment, and emphasis on separation of mind from body, permit, though do not expressly advocate for, the practice of abortion. Further, in certain contemporary contexts, Buddhist practices exist to mitigate the suffering experienced by women who have lost an unborn child, whether through abortion or miscarriage. In modern-day Japan for example, many Buddhists practice mizuko kuyō, a set of formal remembrance rituals, which provides structured support to families in their efforts to mourn, to remember the departed, and to celebrate the redirection of human potential. This contemporary practice is consistent with aforementioned tenets of early Buddhist thought. Although seemingly oxymoronic, the Buddhist view of abortion and the mizuko kuyō rituals are human-centric, not only for the families but also for the redirected. Other societies, cultures, and theological perspectives have and may further benefit from reframing any interpretation of abortion, not as an inherently moral or immoral act (i.e., a binary), but rather as an act overwhelmingly characterized by the complexity of human emotion in the face of unimaginable loss. This humanistic conceptualization of abortion is manifested by the modern Buddhist practice of mizuko kuyō.

Neurodegenerative proteinopathies characterized by intracellular aggregates of tau proteins, termed tauopathies, include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau), and related disorders. Pathological tau proteins derived from human AD brains (AD-tau) act as proteopathic seeds that initiate the templated aggregation of soluble tau upon intracerebral injection into tau transgenic (Tg) and wild-type mice, thereby modeling human tau pathology. In this study, we found that aged Tg mice of both sexes expressing human tau proteins harboring a pathogenic P301LMAPTmutation labeled with green fluorescent protein (T40PL-GFP Tg mouse line) exhibited hyperphosphorylated tau mislocalized to the somatodentritic domain of neurons, but these mice did not developde novoinsoluble tau aggregates, which are characteristic of human AD and related tauopathies. However, intracerebral injections of either T40PL preformed fibrils (PFFs) or AD-tau seeds into T40PL-GFP mice induced abundant intraneuronal pathological inclusions of hyperphosphorylated T40PL-GFP. These injections of pathological tau resulted in the propagation of tau pathology from the injection site to neuroanatomically connected brain regions, and these tau inclusions consisted of both T40PL-GFP and WT endogenous mouse tau. Primary neurons cultured from the brains of neonatal T40PL-GFP mice provided an informativein vitromodel for examining the uptake and localization of tau PFFs. These findings demonstrate the seeded aggregation of T40PL-GFPin vivoby synthetic PFFs and human AD-tau and the utility of this system to study the neuropathological spread of tau aggregates.SIGNIFICANCE STATEMENTThe stereotypical spread of pathological tau protein aggregates have recently been attributed to the transmission of proteopathic seeds. Despite the extensive use of transgenic mouse models to investigate the propagation of tau pathologyin vivo, details of the aggregation process such as the early seeding events leading to new tau pathology have remained elusive. This study validates the use of GFP-labeled tau expressed by neuronsin vivoandin vitroas models for investigating mechanisms underlying the seeded transmission of tau pathology as well as tau-focused drug discovery to identify disease-modifying therapies for AD and related tauopathies.

Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.

Studies have shown an overlap of Aβ plaques, tau tangles, and α-synuclein (α-syn) pathologies in the brains of Alzheimer's disease (AD) and Parkinson's disease (PD) with dementia (PDD) patients, with increased pathological burden correlating with severity of cognitive and motor symptoms. Despite the observed co-pathology and concomitance of motor and cognitive phenotypes, the consequences of the primary amyloidogenic protein on the secondary pathologies remain poorly understood. To better define the relationship between α-syn and Aβ plaques, we injected α-syn preformed fibrils (α-syn mpffs) into mice with abundant Aβ plaques. Aβ deposits dramatically accelerated α-syn pathogenesis and spread throughout the brain. Remarkably, hyperphosphorylated tau (p-tau) was induced in α-syn mpff-injected 5xFAD mice. Finally, α-syn mpff-injected 5xFAD mice showed neuron loss that correlated with the progressive decline of cognitive and motor performance. Our findings suggest a "feed-forward" mechanism whereby Aβ plaques enhance endogenous α-syn seeding and spreading over time post-injection with mpffs.

Objective The aging larynx undergoes structural changes that have functional consequences for voice production known as presbyphonia. Treatment of presbyphonia includes voice therapy and surgery. This review seeks to examine voice outcomes after surgery for presbyphonia. Data sources Three electronic databases (PreMed, ScienceDirect, Embase) were reviewed for articles published between 1 January 1900 and 1 June 2019. Review methods Original English-language studies examining surgical treatment of presbyphonia in elderly patients (≥65 years) were included according to PRISMA. Two researchers independently analyzed articles. Outcome measures were extracted from and qualitatively compared across studies. Results Of the 118 articles identified, five satisfied eligibility criteria. In all studies, diagnosis of presbyphonia was based on videostroboscopy. 85 patients (61M, 21F) were evaluated. 37.6% underwent implantation thyroplasty (IT), 48.2% underwent injection augmentation (IA), 7.1% underwent both, and 7.1% underwent basic-fibroblastic growth factor (b-FGF) injection. Average patient age was 71.3 years. Average follow-up time was 5.4 months. Three months post-intervention, IT patients self-reported greater improvement in quality of life (QoL) metrics compared to IA patients. Aerodynamic measures, like mean phonation time, were significantly improved in IT and IA, but not b-FGF-injected patients. All patients experienced improvements in the auditory perception of voice three months post-intervention. Conclusion Surgical modalities currently utilized for presbyphonia include IT and IA, with bFGF-injection being trialed abroad. IT patients reported enhanced QoL relative to IA and bFGF-injected patients. Overall there is a paucity of high-power, prospective studies that explore the efficacy of these modalities. Moreover, wide variability exists in reported outcomes among published studies.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the most common causes of familial Parkinson’s disease (PD). The most common mutations in the LRRK2 gene induce elevated kinase activity of the LRRK2 protein. Recent studies have also suggested that LRRK2 kinase activity may be elevated in idiopathic PD patients, even in the absence of LRRK2 mutations. LRRK2 is therefore a prime candidate for small molecule kinase inhibitor development. However, it is currently unknown how LRRK2 influences the underlying pathogenesis of PD and how LRRK2 might influence extant pathogenesis. To understand whether LRRK2 inhibition would show some benefit in the absence of LRRK2 mutations, we treated a preclinical mouse model of PD with the potent LRRK2 inhibitor MLi-2. The inhibitor was well-tolerated by mice and dramatically reduced LRRK2 kinase activity. However, LRRK2 inhibition did not reverse motor phenotypes, pathological α-synuclein accumulation or neuron loss. The current study suggests that LRRK2 is not necessary for α-synuclein pathogenesis in this mouse model of PD and that further studies are needed to assess the likely clinical benefit of LRRK2 inhibition in idiopathic PD.