Concerns regarding health-related social media usage amongst otolaryngology patients.

PURPOSE: The objective of this study was to determine concerns of otolaryngology patients regarding health-related social media usage. METHODS: A total of 372 otolaryngology patients were asked to report their level of concern (on a scale of "not at all", "a little", "somewhat", or "highly" concerned) regarding health-related social media usage as it pertained to risk of "loss of privacy or anonymity related to your health condition", "reliability of disease/treatment information", and "reliability of physician reviews/recommendations". Demographics and social media usage patterns (on Facebook, Instagram, Twitter, TikTok or other platforms) were compared to concerns about health-related social media usage. RESULTS: The level of concern was highest for reliability of disease/treatment information and least for loss of privacy/anonymity (p < 0.001). Concern about loss of privacy/anonymity was associated with age over 25 years (OR = 3.12, 95%CI 1.66-5.86, p < 0.001) and negatively with daily use of Twitter (OR = 0.54, 95%CI 0.30-0.96, p = 0.035). Concern about reliability of disease/treatment information was negatively associated with Medicare insurance (OR = 0.57, 95%CI 0.35-0.93, p = 0.024), which is available to adults aged ≥65 years, and concern over reliability of physician reviews/recommendations was associated with patients identifying their race as Asian, American Indian and other (OR = 3.16, 95%CI 1.22-8.19, p = 0.018). CONCLUSIONS: The greatest concern about health-related social media usage is related to reliability of disease/treatment information, though notably less among patients with Medicare who represent adults of age 65 years or older. Concerns over loss of privacy/anonymity and reliability of physician reviews/recommendations are also prevalent and associated with patient demographics. These concerns may constrain utilization of social media for healthcare purposes, which highlights the importance of reliable sources of information.

Anterior occipital condyle screw placement through the endonasal corridor: proof of concept study with cadaveric analysis.

PURPOSE: Odontoidectomy for ventral compressive pathology may result in O-C1 and/or C1-2 instability. Same-stage endonasal C1-2 spinal fusion has been advocated to eliminate risks associated with separate-stage posterior approaches. While endonasal methods for C1 instrumentation and C1-2 trans-articular stabilization exist, no hypothetical construct for endonasal occipital instrumentation has been validated. We provide an anatomic description of anterior occipital condyle (AOC) screw endonasal placement as proof-of-concept for endonasal craniocervical stabilization. METHODS: Eight adult, injected cadaveric heads were studied for placing 16 AOC screws endonasally. Thin-cut CT was used for registration. After turning a standard inferior U-shaped nasopharyngeal flap endonasally, 4 mm × 22 mm AOC screws were placed with a 0° driver using neuronavigation. Post-placement CT scans were obtained to determine: site-of-entry, measured from the endonasal projection of the medial O-C1 joint; screw angulation in sagittal and axial planes, proximity to critical structures. RESULTS: Average site-of-entry was 6.88 mm lateral and 9.74 mm rostral to the medial O-C1 joint. Average angulation in the sagittal plane was 0.16° inferior to the palatal line. Average angulation in the axial plane was 23.97° lateral to midline. Average minimum screw distances from the jugular bulb and hypoglossal canal were 4.80 mm and 1.55 mm. CONCLUSION: Endonasal placement of AOC screws is feasible using a 0° driver. Our measurements provide useful parameters to guide optimal placement. Given proximity of hypoglossal canal and jugular bulb, neuronavigation is recommended. Biomechanical studies will ultimately be necessary to evaluate the strength of AOC screws with plate-screw constructs utilizing endonasal C1 lateral mass or C1-2 trans-articular screws as inferior fixation points.

Case report of bilateral middle ear effusion requiring myringotomy and tube placement following inferior U-shaped nasopharyngeal flap elevation for endonasal odontoidectomy: investigation of causality.

We describe a patient with symptomatic os odontoideum and a previous history of C1-2 wiring who underwent successful treatment with a staged endonasal odontoidectomy and C1-2 revision of instrumentation. Access to the odontoid process was gained through the endonasal corridor using an inverted U-shaped nasopharyngeal flap (IUNF). Post-operatively, the patient experienced resolution of her presenting neurologic symptoms but developed conductive hearing loss secondary to bilateral middle ear effusion, requiring bilateral myringotomy and tube placement 3 months post-operatively. We hypothesize this dysfunction may have resulted from surgical edema, packing buttressing the IUNF, or some combination thereof. In this manuscript, we review the evolution of the nasopharyngeal exposure for odontoidectomy and whether an IUNF may predispose to this complication.

Heterogeneity in the definition of chronic rhinosinusitis disease control: a systematic review of the scientific literature.

PURPOSE: Disease control is conceptually recognized to be an important outcome measure for chronic rhinosinusitis (CRS). However, inconsistent usage is a significant factor in disadoption of important concepts and it is presently unclear how consistently the construct of CRS 'control' is being defined/applied. The objective of this study was to determine the heterogeneity of CRS disease control definitions in the scientific literature. METHODS: Systematic review of PubMed and Web of Science databases from inception through December 31, 2022. Included studies used CRS disease control as an explicitly stated outcome measure. The definitions of CRS disease control were collected. RESULTS: Thirty-one studies were identified with more than half published in 2021 or later. Definitions of CRS control were variable, although 48.4% of studies used the EPOS (2012 or 2020) criteria to define control, 14 other unique definitions of CRS disease control were also implemented. Most studies included the burden CRS symptoms (80.6%), need for antibiotics or systemic corticosteroids (77.4%) or nasal endoscopy findings (61.3%) as criteria in their definitions of CRS disease control. However, the specific combination of these criteria and prior time periods over which they were assessed were highly variable. CONCLUSION: CRS disease control is not consistently defined in the scientific literature. Although many studies conceptually treated 'control' as the goal of CRS treatment, 15 different criteria were used to define CRS disease control, representing significant heterogeneity. Scientific derivation of criteria and collaborative consensus building are needed for the development of a widely-accepted and -applied definition of CRS disease control.

Annual trends in Google searches provides insights related to rhinosinusitis exacerbations.

PURPOSE: Temporal trends of disease-specific internet searches may provide novel insights into seasonal dynamics of disease burden and, by extension, disease pathophysiology. The aim of this study was to define the temporal trends in rhinosinusitis-specific internet searches. METHODS: This was a cross sectional analysis of search volume for predefined search terms. Google trends was used to explore the volume of searches for five specific search terms related to rhinosinusitis: nose, mucus, sinus, sinusitis, chronic sinusitis, which were entered into Google web search between 2004 and 2019. Results were analyzed within search "context" which included temporally associated related searches. Relative search volume (RSV) was analyzed for English and non-English speaking countries from the Northern and Southern hemispheres. Analysis of seasonality was performed using the cosinor model. RESULTS: The five specific search terms were most related to rhinosinusitis-related search contexts, indicating that they were appropriately reflective of internet queries by patients for rhinosinusitis. The RSV for rhinosinusitis-related terms and more general search terms increased with each passing year indicating constant interest in rhinosinusitis. Cosinor time series analysis revealed inquiry peaks in winter months for all five specific rhinosinusitis-related search terms independent from the hemisphere. CONCLUSION: Over a 15-year period, Google searches with rhinosinusitis-specific search terms consistently peaked during the winter around the world. These findings indirectly support the model of viral infection or exposure as the predominant cause of acute rhinosinusitis and acute exacerbations of chronic rhinosinusitis.

Chronic rhinosinusitis disease burden is associated with asthma-related emergency department usage.

PURPOSE: Chronic rhinosinusitis (CRS) disease burden is associated with pulmonary status in asthmatic CRS patients. Asthma-related emergency department (ED) usage is a predictor of asthma-related mortality. We sought to determine whether measures of CRS disease burden are associated with asthma-related ED usage. METHODS: We prospectively recruited 263 asthmatic CRS patients for this cross-sectional study. CRS burden was measured using the 22-item Sinonasal Outcome Test (SNOT-22), and patient-reported CRS-related antibiotic usage and CRS-related oral corticosteroids usage over the preceding year. Asthma-related ED visits over the prior year were also assessed. RESULTS: Of all participants, 18.6% had at least 1 asthma-related ED visit (mean 0.3 ED visits for the whole cohort). Asthma-related ED usage was associated with SNOT-22 score [adjusted rate ratio (RR) = 1.02, 95% CI 1.01-1.03, p = 0.040] and CRS-related oral corticosteroids usage in the past year (RR = 1.52, 95% CI 1.26-1.83, p < 0.001). From the SNOT-22 score, asthma-related ED usage was only associated with the nasal subdomain score (RR = 1.08, 95% CI 1.03-1.13, p = 0.001). These measures of CRS disease burden could be used with good sensitivity and specificity to detect patients with asthma-related ED usage in the past year, the majority of whom were undertreated for their asthma. CONCLUSIONS: Measures of CRS disease burden are associated with and can be used to detect, patients having asthma-related ED usage. These results further solidify the connection between CRS and asthma disease courses, and also present an opportunity to use CRS disease burden as a tool for identifying-and implementing greater treatment of-patients at highest risk for asthma-related mortality.

Patient perspectives on recall period and response options in patient-reported outcome measures for chronic rhinosinusitis symptomatology: A pilot study.

OBJECTIVE: Patient-reported outcome measures (PROMs) for assessment of chronic rhinosinusitis (CRS) employ a variety of recall periods and response scales for reporting CRS symptom burden. CRS patient perspective is unknown with respect to recall periods and response scales in PROMs. DESIGN: Cross-sectional study. SETTING: Tertiary rhinology clinic. PARTICIPANTS: Sixty three adults with CRS. MAIN OUTCOME MEASURES: Participants were asked to choose which CRS symptom recall period-1 day, 2 weeks, 1 month or greater than 1 month-was most reflective of their current disease state and best to base treatment recommendations (including surgery) upon. Participants were also asked to report which of six response scales (one visual analogue scale [VAS] and five Likert scales ranging from four to eight items) were easiest to use and understand, and most preferred. RESULTS: A majority of participants felt the current state of their CRS symptoms was best reflected by a recall period of 2 weeks to 1 month; however, patients preferred that recommendations about treatments, including endoscopic sinus surgery, be determined by symptoms experienced over at least a one-month period. Participants generally found the VAS and seven-item Likert scale to be the easiest to use and understand, and their most preferred scales. No patient characteristics associated with preferences for recall periods or response scales. CONCLUSION: Future PROMs for CRS symptoms should consider assessment of symptoms over a one-month time frame and use either a VAS or seven-item Likert response scale to optimally balance reflection of current disease state, need for intervention and patient preference.

Characterising the potential for recall bias in anchor-based MCID calculation of patient-reported outcome measures for chronic rhinosinusitis.

OBJECTIVE: Anchor-based methods to calculate the minimal clinically important difference (MCID) of a patient-reported outcome measure (PROM) may suffer from recall bias. This has never been investigated for otolaryngic PROMs. We sought to identify evidence of recall bias in calculation of MCIDs of PROMs for patients with chronic rhinosinusitis (CRS). DESIGN: Retrospective analysis of data from two previous studies calculating the MCID of the 22-item Sinonasal Outcome Test (SNOT-22) and 5-dimensonal EuroQol questionnaire (EQ-5D) in CRS patients. SETTING: Tertiary rhinology clinic. PARTICIPANTS: Adults with CRS. MAIN OUTCOME MEASURES: SNOT-22 score, and EQ-5D visual analog scale scores (EQ-5D VAS) and health utility values (EQ-5D HUV) before and after medical treatment for CRS. After treatment, participants were asked to rate the change in sinonasal symptoms and general health (the anchor question) as "Much worse," "A little worse," "About the same," "A little better" or "Much better." Participants' responses to the anchor question were checked for association with post-treatment and pre-treatment scores using ordinal regression. RESULTS: On univariate association, post-treatment SNOT-22 and EQ-5D scores were associated with respective participants' anchor question responses (P < .001 in all cases). Only pre-treatment SNOT-22 score was associated with anchor question responses (P = .017) on univariate association, in contrast to pre-treatment EQ-5D scores. Pre-treatment EQ-5D scores only associated with anchor question responses when controlling for post-treatment scores. CONCLUSION: The anchor-based MCIDs of the SNOT-22, which reflects disease-specific QOL, and the EQ-5D, which reflects general health-related QOL, appear to be largely free of recall bias.

Role of the central lysine cluster and scrapie templating in the transmissibility of synthetic prion protein aggregates.

Mammalian prion structures and replication mechanisms are poorly understood. Most synthetic recombinant prion protein (rPrP) amyloids prepared without cofactors are non-infectious or much less infectious than bona fide tissue-derived PrPSc. This effect has been associated with differences in folding of the aggregates, manifested in part by reduced solvent exclusion and protease-resistance in rPrP amyloids, especially within residues ~90-160. Substitution of 4 lysines within residues 101-110 of rPrP (central lysine cluster) with alanines (K4A) or asparagines (K4N) allows formation of aggregates with extended proteinase K (PK) resistant cores reminiscent of PrPSc, particularly when seeded with PrPSc. Here we have compared the infectivity of rPrP aggregates made with K4N, K4A or wild-type (WT) rPrP, after seeding with scrapie brain homogenate (ScBH) or normal brain homogenate (NBH). None of these preparations caused clinical disease on first passage into rodents. However, the ScBH-seeded fibrils (only) led to a subclinical pathogenesis as indicated by increases in prion seeding activity, neuropathology, and abnormal PrP in the brain. Seeding activities usually accumulated to much higher levels in animals inoculated with ScBH-seeded fibrils made with the K4N, rather than WT, rPrP molecules. Brain homogenates from subclinical animals induced clinical disease on second passage into "hamsterized" Tg7 mice, with shorter incubation times in animals inoculated with ScBH-seeded K4N rPrP fibrils. On second passage from animals inoculated with ScBH-seeded WT fibrils, we detected an additional PK resistant PrP fragment that was similar to that of bona fide PrPSc. Together these data indicate that both the central lysine cluster and scrapie seeding of rPrP aggregates influence the induction of PrP misfolding, neuropathology and clinical manifestations upon passage in vivo. We confirm that some rPrP aggregates can initiate further aggregation without typical pathogenesis in vivo. We also provide evidence that there is little, if any, biohazard associated with routine RT-QuIC assays.

Seasonal variations in chronic rhinosinusitis symptom burden may be explained by changes in mood.

PURPOSE: There are many year-round modifiers of chronic rhinosinusitis (CRS). However, it is unknown whether there are seasonal variations in the sinonasal symptom burden of CRS. METHODS: This was a retrospective cross-sectional study of sinonasal symptom burden measured using the 22-item Sinonasal Outcome Test (SNOT-22) and its four associated nasal, sleep, ear/facial discomfort and emotional subdomains in 1028 individuals with CRS. The season (winter, spring, summer or fall) when the SNOT-22 was completed was recorded. Regressions, controlling for clinical and demographic characteristics, were performed to seek association between season of the year and SNOT-22 total and subdomain scores. RESULTS: The mean SNOT-22 scores were 37.4 for those individuals completing their SNOT-22 in the fall, 40.5 in the winter, 37.4 in the spring and 36.0 in the summer. There was a statistically significant association between higher SNOT-22 scores and completing the SNOT-22 in the wintertime (adjusted ß = 4.08, 95% CI 0.74-7.42, p = 0.017). When seeking association between season and SNOT-22 subdomain scores, wintertime was associated only with higher emotional (adjusted ß = 0.48, 95% CI 0.14-0.81, p = 0.006) and sleep (adjusted ß = 2.23, 95% CI 0.54-3.91, p = 0.010) subdomain scores. Examining individual SNOT-22 items, these associations were due to more symptoms related to depressed mood ("sad") and psychomotor retardation. CONCLUSION: There are seasonal variations in symptom burden of CRS patients, independent of aeroallergen hypersensitivity, with the greatest increase in baseline CRS symptomatology during the winter. This finding was most strongly associated with increased emotional symptomatology and depressed mood.

Longitudinal improvement in nasal obstruction symptoms of chronic rhinosinusitis directly associates with improvement in mood.

PURPOSE: The effects of nasal obstruction in patients with chronic rhinosinusitis (CRS) are associated with depressed mood. We sought to validate this finding by determining whether improvement in nasal obstruction would translate to improvement in depressed mood. METHODS: This was a prospective observational study of 150 patients undergoing medical management for CRS. Data were collected at two timepoints: enrollment and a subsequent follow-up visit 3-12 months later. Impact of nasal obstruction was measured using the Nasal Obstruction Symptom Evaluation (NOSE) instrument and depressed mood was measured using the 2-item Patient Health Questionnaire (PHQ-2). Sinonasal symptoms associated with CRS were also measured using the 22-item Sinonasal Outcome Test (SNOT-22). Clinical and demographic characteristics were collected. The relationship between changes in PHQ-2 and NOSE scores was determined with correlation and linear regression. RESULTS: Change in PHQ-2 score was significantly correlated with change in NOSE score (ρ = 0.30, p < 0.001). After controlling for covariates, change in PHQ-2 score was associated with change in NOSE score (adjusted linear regression coefficient [ß] = 0.014, 95% CI 0.006-0.022, p = 0.001). We confirmed these relationships, finding that change in PHQ-2 was associated (adjusted ß = 0.037, 95% CI 0.013-0.061, p = 0.003) with change in the nasal subdomain score of the SNOT-22. Improvement in NOSE score by greater than 22 points was predictive of improvement in PHQ-2 score with sensitivity 54.5% and 83.8% specificity (p < 0.001). CONCLUSION: These results provide evidence that improvements in nasal manifestations/symptoms of CRS translate to significant improvements in mood.

Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.

Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice.

Inactivation of Prions and Amyloid Seeds with Hypochlorous Acid.

Hypochlorous acid (HOCl) is produced naturally by neutrophils and other cells to kill conventional microbes in vivo. Synthetic preparations containing HOCl can also be effective as microbial disinfectants. Here we have tested whether HOCl can also inactivate prions and other self-propagating protein amyloid seeds. Prions are deadly pathogens that are notoriously difficult to inactivate, and standard microbial disinfection protocols are often inadequate. Recommended treatments for prion decontamination include strongly basic (pH ≥~12) sodium hypochlorite bleach, ≥1 N sodium hydroxide, and/or prolonged autoclaving. These treatments are damaging and/or unsuitable for many clinical, agricultural and environmental applications. We have tested the anti-prion activity of a weakly acidic aqueous formulation of HOCl (BrioHOCl) that poses no apparent hazard to either users or many surfaces. For example, BrioHOCl can be applied directly to skin and mucous membranes and has been aerosolized to treat entire rooms without apparent deleterious effects. Here, we demonstrate that immersion in BrioHOCl can inactivate not only a range of target microbes, including spores of Bacillus subtilis, but also prions in tissue suspensions and on stainless steel. Real-time quaking-induced conversion (RT-QuIC) assays showed that BrioHOCl treatments eliminated all detectable prion seeding activity of human Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, cervine chronic wasting disease, sheep scrapie and hamster scrapie; these findings indicated reductions of ≥103- to 106-fold. Transgenic mouse bioassays showed that all detectable hamster-adapted scrapie infectivity in brain homogenates or on steel wires was eliminated, representing reductions of ≥~105.75-fold and >104-fold, respectively. Inactivation of RT-QuIC seeding activity correlated with free chlorine concentration and higher order aggregation or destruction of proteins generally, including prion protein. BrioHOCl treatments had similar effects on amyloids composed of human α-synuclein and a fragment of human tau. These results indicate that HOCl can block the self-propagating activity of prions and other amyloids.

Changes in chronic rhinosinusitis symptoms differentially associate with improvement in general health-related quality of life.

BACKGROUND: Previous work has shown that the symptoms of chronic rhinosinusitis (CRS) differentially associate with decreased general health-related quality of life (QOL). OBJECTIVE: We sought to determine whether longitudinal changes in different types of CRS symptomatology lead to correspondingly different magnitude changes in general health-related QOL. METHODS: Prospective observational study of 145 patients undergoing medical management for CRS. Chronic rhinosinusitis symptom severity was measured using the 22-item Sinonasal Outcome Test (SNOT-22) and associated nasal, sleep, ear/facial discomfort, and emotional subdomains of the SNOT-22. General health-related QOL was measured using the 5-dimensional EuroQoL questionnaire's visual analog scale (EQ-5D VAS). These data were collected at 2 time points: at enrollment and at a subsequent follow-up visit within the next 2 to 6 months. Associations were sought between the changes in SNOT-22 and EQ-5D VAS. RESULTS: The change in SNOT-22 was associated with change in EQ-5D VAS (adjusted linear regression coefficient [ß] = -0.37, 95%CI: -0.51 to -0.24, P < .001). The change in EQ-5D VAS was only associated with changes in the sleep (adjusted ß = -0.42, 95% confidence interval [95%CI]: -0.81 to -0.04, P = .034) and ear/facial discomfort (adjusted ß = -1.00, 95%CI: -1.89 to -0.10, P = .031) subdomains but not nasal (adjusted ß = -0.12, 95%CI: -0.52 to 0.28, P = .564) or emotional (adjusted ß = -0.17, 95%CI: -1.83 to 1.49, P = .840) subdomains. CONCLUSION: Changes in the severity of sleep and ear/facial discomfort symptoms associate most greatly with the change in general health-related QOL that CRS patients experience during routine medical management. Reduction of these extranasal symptoms of CRS may therefore lead to the greatest improvement in general health-related QOL.

Minimal clinically important difference for the 22-item Sinonasal Outcome Test in medically managed patients with chronic rhinosinusitis.

OBJECTIVE: To determine the minimal clinically important difference (MCID) of the 22-item Sinonasal Outcome Test (SNOT-22) in individuals undergoing medical management for their chronic rhinosinusitis (CRS). DESIGN: Prospective observational study. SETTING: Academic, tertiary care centre. PARTICIPANTS: A total of 247 adults undergoing medical management for CRS. MAIN OUTCOME MEASURE: At enrolment, participants completed a SNOT-22. At a subsequent follow-up visit, 2-12 months after enrolment, participants also completed a SNOT-22. At follow-up, participants also rated the change in their sinus symptoms and general health as "Much worse," "A little worse," "About the same," "A little better" or "Much better" compared with enrolment; these two questions were used as sinus symptom and general health anchor questions, respectively. The SNOT-22 MCID was calculated using distribution-based, anchor-based and receiver operating characteristic (ROC) curve-based methods. RESULTS: Using the distribution-based method, the SNOT-22 MCID was 11.6. Using the sinus symptom anchor question, the SNOT-22 MCID was 10.5; applying the ROC method to the sinus symptom anchor yielded an MCID of 12.5. In comparison, using the general health anchor question, the SNOT-22 MCID was 8.3; applying the ROC method to the sinus symptom anchor yielded an MCID of 17.5. In all cases, the calculated MCID had a sensitivity of approximately 50-60% and specificity of approximately 80-90%. CONCLUSIONS: Based on our results, we propose a SNOT-22 MCID of 12 in medically managed patients with CRS. The MCID, while specific, was not sensitive for identifying patients with CRS experiencing a noticeable improvement in sinus symptoms or general health.

Statins are ineffective at reducing neuroinflammation or prolonging survival in scrapie-infected mice.

Neuroinflammation is a prominent component of several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, tauopathies, amyotrophic lateral sclerosis and prion diseases. In such conditions, the ability to decrease neuroinflammation by drug therapy may influence disease progression. Statins have been used to treat hyperlipidemia as well as reduce neuroinflammation and oxidative stress in various tissues. In previous studies, treatment of scrapie-infected mice with the type 1 statins, simvastatin or pravastatin, showed a small beneficial effect on survival time. In the current study, to increase the effectiveness of statin therapy, we treated infected mice with atorvastatin, a type 2 statin that has improved pharmacokinetics over many type 1 statins. Treatments with either simvastatin or pravastatin were tested for comparison. We evaluated scrapie-infected mice for protease-resistant PrP (PrPres) accumulation, gliosis, neuroinflammation and time until advanced clinical disease requiring euthanasia. All three statin treatments reduced total serum cholesterol ≥40 % in mice. However, gliosis and PrPres deposition were similar in statin-treated and untreated infected mice. Time to euthanasia due to advanced clinical signs was not changed in statin-treated mice relative to untreated mice, a finding at odds with previous reports. Expression of 84 inflammatory genes involved in neuroinflammation was also quantitated. Seven genes were reduced by pravastatin, and one gene was reduced by atorvastatin. In contrast, simvastatin therapy did not reduce any of the tested genes, but did slightly increase the expression of Ccl2 and Cxcl13. Our studies indicate that none of the three statins tested were effective in reducing scrapie-induced neuroinflammation or neuropathogenesis.

Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo.

UNLABELLED: Although all 12 subtypes of human interferon alpha (IFN-α) bind the same receptor, recent results have demonstrated that they elicit unique host responses and display distinct efficacies in the control of different viral infections. The IFN-α2 subtype is currently in HIV-1 clinical trials, but it has not consistently reduced viral loads in HIV-1 patients and is not the most effective subtype against HIV-1 in vitro We now demonstrate in humanized mice that, when delivered at the same high clinical dose, the human IFN-α14 subtype has very potent anti-HIV-1 activity whereas IFN-α2 does not. In both postexposure prophylaxis and treatment of acute infections, IFN-α14, but not IFN-α2, significantly suppressed HIV-1 replication and proviral loads. Furthermore, HIV-1-induced immune hyperactivation, which is a prognosticator of disease progression, was reduced by IFN-α14 but not IFN-α2. Whereas ineffective IFN-α2 therapy was associated with CD8(+) T cell activation, successful IFN-α14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of tetherin and MX2, increased APOBEC3G signature mutations in HIV-1 proviral DNA, and higher frequencies of TRAIL(+) NK cells. These results identify IFN-α14 as a potent new therapeutic that operates via mechanisms distinct from those of antiretroviral drugs. The ability of IFN-α14 to reduce both viremia and proviral loads in vivo suggests that it has strong potential as a component of a cure strategy for HIV-1 infections. The broad implication of these results is that the antiviral efficacy of each individual IFN-α subtype should be evaluated against the specific virus being treated. IMPORTANCE: The naturally occurring antiviral protein IFN-α2 is used to treat hepatitis viruses but has proven rather ineffective against HIV in comparison to triple therapy with the antiretroviral (ARV) drugs. Although ARVs suppress the replication of HIV, they fail to completely clear infections. Since IFN-α acts by different mechanism than ARVs and has been shown to reduce HIV proviral loads, clinical trials are under way to test whether IFN-α2 combined with ARVs might eradicate HIV-1 infections. IFN-α is actually a family of 12 distinct proteins, and each IFN-α subtype has different efficacies toward different viruses. Here, we use mice that contain a human immune system, so they can be infected with HIV. With this model, we demonstrate that while IFN-α2 is only weakly effective against HIV, IFN-α14 is extremely potent. This discovery identifies IFN-α14 as a more powerful IFN-α subtype for use in combination therapy trials aimed toward an HIV cure.

Depression symptoms and lost productivity in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is associated with significant losses of patient productivity that cost billions of dollars every year. The causative factors for decreases in productivity in patients with CRS have yet to be determined. OBJECTIVE: To determine which patterns of CRS symptoms drive lost productivity. METHODS: Prospective, cross-sectional cohort study of 107 patients with CRS. Sinonasal symptom severity was measured using the 22-item Sinonasal Outcomes Test, from which sleep, nasal, otologic or facial pain, and emotional function subdomain scores were calculated using principal component analysis. Depression risk was assessed with the 2-item Patient Health Questionnaire (PHQ-2), whereas nasal obstruction was assessed with the Nasal Obstruction Symptom Evaluation (NOSE) instrument. Lost productivity was assessed by asking participants how many days of work and/or school they missed in the last 3 months because of CRS. Associations were sought between lost productivity and CRS symptoms. RESULTS: A total of 107 patients were recruited. Patients missed a mean (SD) of 3.1 (12.9) days of work or school because of CRS. Lost productivity was most strongly associated with the emotional function subdomain (ß = 7.48; 95% confidence interval [CI], 5.71-9.25; P < .001). Reinforcing this finding, lost productivity was associated with PHQ-2 score (ß = 4.72; 95% CI, 2.62-6.83; P < .001). Lost productivity was less strongly associated with the nasal symptom subdomain score (ß = 2.65; 95% CI, 0.77-4.52; P = .007), and there was no association between lost productivity and NOSE score (ß = 0.01; 95% CI, -0.12 to 0.13; P = .91). CONCLUSION: Symptoms associated with depression are most strongly associated with missed days of work or school because of CRS. Further treatment focusing on depression-associated symptoms in patients with CRS may reduce losses in productivity.

Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice.

Microglial activation is a hallmark of the neuroimmunological response to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. The CX3C chemokine axis consists of fractalkine (CX3CL1) and its receptor (CX3CR1); these are expressed by neurons and microglia respectively, and are known to modulate microglial activation. In prion-infected mice, both Cx3cr1 and Cx3cl1 are altered, suggesting a role in disease. To investigate the influence of CX3C axis signalling on prion disease, we infected Cx3cr1 knockout (Cx3cr1-KO) and control mice with scrapie strains 22L and RML. Deletion of Cx3cr1 had no effect on development of clinical signs or disease incubation period. In addition, comparison of brain tissue from Cx3cr1-KO and control mice revealed no significant differences in cytokine levels, spongiosis, deposition of disease-associated prion protein or microglial activation. Thus, microglial activation during prion infection did not require CX3C axis signalling.