Subunit vaccines with a saponin-based adjuvant boost humoral and cellular immunity to MERS coronavirus.

Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks have constituted a public health issue with drastic mortality higher than 34%, necessitating the development of an effective vaccine. During MERS-CoV infection, the trimeric spike protein on the viral envelope is primarily responsible for attachment to host cellular receptor, dipeptidyl peptidase 4 (DPP4). With the goal of generating a protein-based prophylactic, we designed a subunit vaccine comprising the recombinant S1 protein with a trimerization motif (S1-Fd) and examined its immunogenicity and protective immune responses in combination with various adjuvants. We found that sera from immunized wild-type and human DPP4 transgenic mice contained S1-specific antibodies that can neutralize MERS-CoV infection in susceptible cells. Vaccination with S1-Fd protein in combination with a saponin-based QS-21 adjuvant provided long-term humoral as well as cellular immunity in mice. Our findings highlight the significance of the trimeric S1 protein in the development of MERS-CoV vaccines and offer a suitable adjuvant, QS-21, to induce robust and prolonged memory T cell response.

Is there a clinical difference in paediatric congenital cholesteatoma according to age?

OBJECTIVE: This study aimed to analyse surgical outcomes of paediatric patients with congenital cholesteatoma according to age. METHOD: This was a retrospective study reviewing the records of 186 children (136 boys and 50 girls) from August 1993 to January 2016. Patients were divided into three age groups (equal to or less than 3 years, over 3 and less than 7 years, and 7 to 15 years). RESULTS: There were significant differences in chief complaints, location of cholesteatoma in the middle ear, computed tomography findings, operation methods, ossicular erosion and type of cholesteatoma sac among the three groups. In addition, older age, open type cholesteatoma, ossicular erosion and mastoid invasion of cholesteatoma increased the recurrence rate after surgery. However, despite higher pre-operative air-bone gap in older children, hearing can be improved enough after proper surgery with ossicular reconstruction. CONCLUSION: Delayed detection of paediatric cholesteatoma can lead to extensive disease and the need for an aggressive operation, which can result in worse hearing outcomes and an increased recurrence risk.

Vestibular Migraine.

PURPOSE OF REVIEW: To explore recent developments in vestibular migraine (VM). RECENT FINDINGS: This review discusses the current diagnostic criteria for VM in the adult and pediatric populations, as proposed by the International Headache Society and Bárány Society. Recent VM studies confirm the prior findings and reveal new insights, including the wide range of vestibular symptoms, symptoms in the attack-free period, and triggers. Many patients experience persistent vestibular symptoms, even in the absence of acute attacks, which often significantly impact patients' quality of life. The syndrome of benign recurrent vertigo and its relationship to migraine, VM, and Meniere's disease is also discussed. There is a dearth of randomized controlled trials in VM treatment. Prospective and retrospective studies support the benefit of many migraine treatments are effective in VM, including neuromodulation, and calcitonin gene-related peptide monoclonal antibodies. VM affects almost 3% of the population, but remains under-diagnosed. Recent diagnostic criteria can help clinicians diagnose VM in adults and children.

Hospital Occupancy and its Effect on Emergency Department Evaluation.

STUDY OBJECTIVE: To examine whether hospital occupancy was associated with increased testing and treatment during emergency department (ED) evaluations, resulting in reduced admissions. METHODS: We analyzed the electronic health records of an urban academic ED. We linked data from all ED visits from October 1, 2010, to May 29, 2015, with daily hospital occupancy (inpatients/total staffed beds). Outcome measures included the frequency of laboratory testing, advanced imaging, medication administration, and hospitalizations. We modeled each outcome using multivariable negative binomial or logistic regression, as appropriate, and examined their association with daily hospital occupancy quartiles, controlling for patient and visit characteristics. We calculated the adjusted outcome rates and relative changes at each daily hospital occupancy quartile using marginal estimating methods. RESULTS: We included 270,434 ED visits with a mean patient age of 48.1 (standard deviation 19.8) years; 40.1% were female, 22.8% were non-Hispanic Black, and 51.5% were commercially insured. Hospital occupancy was not associated with differences in laboratory testing, advanced imaging, or medication administration. Compared with the first quartile, the third and fourth quartiles of daily hospital occupancy were associated with decreases of 1.5% (95% confidence interval [CI] -2.9 to -0.2; absolute change -0.6 percentage points [95% CI -1.2 to -0.1]) and 4.6% (95% CI -6.0 to -3.2; absolute change -1.9 percentage points [95% CI -2.5 to -1.3]) in hospitalizations, respectively. CONCLUSION: The lack of association between hospital occupancy and laboratory testing, advanced imaging, and medication administration suggest that changes in ED testing or treatment did not facilitate the decrease in admissions during periods of high hospital occupancy.

The Neuropsychology of Dizziness and Related Disorders.

There is a reciprocal relationship between vestibular and neuropsychological disorders. People with vertigo and dizziness are at higher risk of various psychiatric disorders, particularly anxiety, depression, and panic disorder. On the other hand, people with mood disorders are at higher risk of experiencing vertigo and dizziness. Vestibular information plays a crucial role in cognitive processes, especially visuo-spatial abilities. Consequently, vestibular disorders (both peripheral and central) often result in visuo-spatial deficits. In addition, lesions of the cortical and subcortical components of the vestibular system result in disorders of higher vestibular function, such as hemispatial neglect, pusher syndrome, and topographagnosia.

LMBD1 protein participates in cell mitosis by regulating microtubule assembly.

LMBD1 was previously demonstrated to regulate the endocytosis of insulin receptor on the cell surface and to mediate the export of cobalamin from the lysosomes to the cytosol, but little is known about its function in mitosis. In this study, interactome analysis data indicate that LMBD1 is involved in cytoskeleton regulation. Both immunoprecipitation and GST pulldown assays demonstrated the association of LMBD1 with tubulin. Immunofluorescence staining also showed the colocalization of LMBD1 with microtubule in both interphase and mitotic cells. LMBD1 specifically accelerates microtubule assembly dynamics in vitro and antagonizes the microtubule-disruptive effect of vinblastine. In addition, LMBRD1-knockdown impairs mitotic spindle formation, inhibits tubulin polymerization, and diminishes the mitosis-associated tubulin acetylation. The reduced acetylation can be reversed by ectopic expression of LMBD1 protein. These results suggest that LMBD1 protein stabilizes microtubule intermediates. Furthermore, embryonic fibroblasts derived from Lmbrd1 heterozygous knockout mice showed abnormality in microtubule formation, mitosis, and cell growth. Taken together, LMBD1 plays a pivotal role in regulating microtubule assembly that is essential for the process of cell mitosis.

Transient postoperative glycosuria after isoflurane exposure in two dogs.

The present report describes two surgical cases involving the development of sudden glycosuria after isoflurane anaesthesia, despite the dogs having normal blood glucose levels and renal glucose reabsorption. The glycosuria manifested 1 day after surgery and resolved spontaneously within 2 days in both cases. Considering that the surgeries (subcutaneous mandibular mass removal and fracture repair) were unrelated to the kidneys, and there were no remarkable events during anaesthesia, the glycosuria may have been associated with the isoflurane anaesthesia. There have been several previous reports of glycosuria in human patients following transient proximal tubule dysfunction due to volatile anaesthetics. This case report suggests the possibility of transient renal dysfunction following isoflurane anaesthesia in these two clinically healthy dogs. However, considering the observational nature of this report, it can not be excluded that any other procedure performed in these animals was responsible of the observed glycosuria.

Care Gaps and Recommendations in Vestibular Migraine: An Expert Panel Summit.

Vestibular migraine (VM) is an increasingly recognized pathology yet remains as an underdiagnosed cause of vestibular disorders. While current diagnostic criteria are codified in the 2012 Barany Society document and included in the third edition of the international classification of headache disorders, the pathophysiology of this disorder is still elusive. The Association for Migraine Disorders hosted a multidisciplinary, international expert workshop in October 2020 and identified seven current care gaps that the scientific community needs to resolve, including a better understanding of the range of symptoms and phenotypes of VM, the lack of a diagnostic marker, a better understanding of pathophysiologic mechanisms, as well as the lack of clear recommendations for interventions (nonpharmacologic and pharmacologic) and finally, the need for specific outcome measures that will guide clinicians as well as research into the efficacy of interventions. The expert group issued several recommendations to address those areas including establishing a global VM registry, creating an improved diagnostic algorithm using available vestibular tests as well as others that are in development, conducting appropriate trials of high quality to validate current clinically available treatment and fostering collaborative efforts to elucidate the pathophysiologic mechanisms underlying VM, specifically the role of the trigemino-vascular pathways.

Nystagmus and Vertigo in Acute Vestibular Migraine Attacks: Response to Non-Invasive Vagus Nerve Stimulation.

OBJECTIVE: Vestibular migraine (VM) is the most common neurologic cause of vertigo in adults, but there are no currently-approved rescue therapies. This study describes the benefits of non-invasive vagus nerve stimulation (nVNS) on vertigo, headache, and nystagmus during VM attacks. METHODS: Case series of four VM patients who were evaluated during acute VM episodes in a tertiary referral neurology clinic between February 2019 and January 2020. They underwent bedside neuro-otologic examination, and graded the severity of vertigo and headache using a 10-point visual-analog scale (VAS; 0-no symptoms, 10-worst ever symptoms), before and 15 minutes after nVNS. RESULTS: Average vertigo severity was 5 (median 4.5) before, and 1.5 (median 0.5) after nVNS. Mean headache severity (three patients) before treatment was 4 (median 4), and 0.7 (median 0) after. Spontaneous right-beating nystagmus (Patient 1) nystagmus, upbeat nystagmus (Patient 2), and positional nystagmus (Patient 3) resolved with nVNS. Baseline left-beating nystagmus in Patient 4 from previous vestibular neuritis damped during acute VM but returned to baseline following nVNS. In all four patients, ictal nystagmus resolved, and examination findings returned to baseline. CONCLUSIONS: This study suggests nVNS may ameliorate vertigo and headache, as well as nystagmus associated with VM attacks. Larger, sham device-controlled studies are needed to elucidate the benefits of nVNS in VM.

The Interconnections of Mal de Débarquement Syndrome and Vestibular Migraine.

OBJECTIVES/HYPOTHESIS: Mal de débarquement syndrome (MDDS) is characterized by a persistent rocking sensation, as though on a boat. It may occur following exposure to passive motion (motion-triggered MDDS [MT-MDDS]), or spontaneously (spontaneous-onset MDDS [SO-MDDS]). This study investigated the characteristics of MDDS patients with vestibular migraine (MDDS-VM) to those without (MDDS-O). STUDY DESIGN: Retrospective review. METHODS: Retrospective, single-center study of 62 patients with MDDS. Clinical characteristics, Dizziness Handicap Inventory (DHI), Migraine Disability Assessment Score (MIDAS), job impact, and optimal treatment(s) were studied. RESULTS: There were 23 MDDS-O (19 women), and 39 MDDS-VM (35 women) patients. Comparisons between MDDS-VM and MDDS-O showed significant differences in age of onset (41 vs. 52 years, P = .005), interictal visually induced dizziness (89.7% vs. 30.4%, P < .001), interictal head motion-induced dizziness (87.2% vs. 47.8%, P = .001), other vestibular sensations (59% vs. 13%, P < .001), interictal aural symptoms (25.6% vs. 0%, P = .008), number of interictal symptoms (4.3 vs. 2.3, P < .001), total DHI score (54.9 vs. 38.1, P = .005), DHI-P (physical domain) score (16.1 vs. 10, P = .004), DHI-F (functional domain) score (20.9 vs. 15.7, P = .016 MIDAS (4.6 vs. 32, P = .002), and job resignations (23.2% vs. 5%, P = .016). On the other hand, between-group comparisons for MT-MDDS and SO-MDDS did not reveal any significant differences whatsoever. For optimal treatment, venlafaxine was the most used (27.3%) in all groups. For MDDS-VM, antiepileptic drugs and migraine preventive vitamins were also useful in relieving symptoms. CONCLUSIONS: MDDS-VM patients appear to be more disabled than MDDS-O, in terms of severity of dizziness, job impact, and number of symptoms, but have good potential for improvement, particularly with migraine prophylactic treatment. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E1653-E1661, 2021.

Search for Sub-eV Sterile Neutrinos at RENO.

We report a search result for a light sterile neutrino oscillation with roughly 2200 live days of data in the RENO experiment. The search is performed by electron antineutrino (ν[over ¯]_{e}) disappearance taking place between six 2.8 GW_{th} reactors and two identical detectors located at 294 m (near) and 1383 m (far) from the center of the reactor array. A spectral comparison between near and far detectors can explore reactor ν[over ¯]_{e} oscillations to a light sterile neutrino. An observed spectral difference is found to be consistent with that of the three-flavor oscillation model. This yields limits on sin^{2}2θ_{14} in the 10^{-4}≲|Δm_{41}^{2}|≲0.5 eV^{2} region, free from reactor ν[over ¯]_{e} flux and spectrum uncertainties. The RENO result provides the most stringent limits on sterile neutrino mixing at |Δm_{41}^{2}|≲0.002 eV^{2} using the ν[over ¯]_{e} disappearance channel.

Quantitative ultrasound of the tongue: Echo intensity is a potential biomarker of bulbar dysfunction in amyotrophic lateral sclerosis.

OBJECTIVES: To learn if quantitative ultrasound (QUS) distinguishes the tongues of healthy participants and amyotrophic lateral sclerosis (ALS) patients by echo intensity (EI) and to evaluate if EI correlates with measures of bulbar function. METHODS: Ultrasound was performed along the midline of the anterior tongue surface in 16 ALS patients and 16 age-matched controls using a linear hockey stick 16-7 MHz transducer. A region of interest was manually drawn and then EI was determined for the upper 1/3 of the muscle. For patients, the ALS functional rating scale - revised (ALSFRS-R) was used to calculate bulbar sub-scores and the Iowa Oral Performance Instrument (IOPI) was used to measure tongue strength. RESULTS: EI was significantly higher in ALS patients than in healthy participants (49.8 versus 37.8 arbitrary units, p < 0.01). In the patient group, EI was negatively correlated with ALSFRS-R bulbar sub-score (RS = -0.65, p < 0.01). An inverse correlation between EI and tongue strength did not reach significance (RS = -0.34, p = 0.28). CONCLUSIONS: This study suggests that EI can differentiate healthy from diseased tongue muscle, and correlates with a standard functional measure in ALS patients. SIGNIFICANCE: Tongue EI may represent a novel biomarker for bulbar dysfunction in ALS.

Middle East Respiratory Syndrome Coronavirus Nucleocapsid Protein Suppresses Type I and Type III Interferon Induction by Targeting RIG-I Signaling.

Type I and type III interferons (IFNs) are the frontline of antiviral defense mechanisms that trigger hundreds of downstream antiviral genes. In this study, we observed that MERS-CoV nucleocapsid (N) protein suppresses type I and type III IFN gene expression. The N protein suppresses Sendai virus-induced IFN-ß and IFN-λ1 by reducing their promoter activity and mRNA levels, as well as downstream IFN-stimulated genes (ISGs). Retinoic acid-inducible gene I (RIG-I) is known to recognize viral RNA and induce IFN expression through tripartite motif-containing protein 25 (TRIM25)-mediated ubiquitination of RIG-I caspase activation and recruitment domains (CARDs). We discovered that MERS-CoV N protein suppresses RIG-I-CARD-induced, but not MDA5-CARD-induced, IFN-ß and IFN-λ1 promoter activity. By interacting with TRIM25, N protein impedes RIG-I ubiquitination and activation and inhibits the phosphorylation of transcription factors IFN-regulatory factor 3 (IRF3) and NF-κB that are known to be important for IFN gene activation. By employing a recombinant Sindbis virus-EGFP replication system, we showed that viral N protein downregulated the production of not only IFN mRNA but also bioactive IFN proteins. Taken together, MERS-CoV N protein functions as an IFN antagonist. It suppresses RIG-I-induced type I and type III IFN production by interfering with TRIM25-mediated RIG-I ubiquitination. Our study sheds light on the pathogenic mechanism of how MERS-CoV causes disease.IMPORTANCE MERS-CoV causes death of about 35% of patients. Published studies showed that some coronaviruses are capable of suppressing interferon (IFN) expression in the early phase of infection and MERS-CoV proteins can modulate host immune response. In this study, we demonstrated that MERS-CoV nucleocapsid (N) protein suppresses the production of both type I and type III IFNs via sequestering TRIM25, an E3 ubiquitin ligase that is essential for activating the RIG-I signaling pathway. Ectopic expression of TRIM25 rescues the suppressive effect of the N protein. In addition, the C-terminal domain of the viral N protein plays a pivotal role in the suppression of IFN-ß promoter activity. Our findings reveal how MERS-CoV evades innate immunity and provide insights into the interplay between host immune response and viral pathogenicity.

Romosozumab or alendronate for fracture prevention in East Asian patients: a subanalysis of the phase III, randomized ARCH study.

Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. Among high-risk postmenopausal East Asian women, romosozumab followed by alendronate was associated with lower incidences of fractures vs alendronate alone. Romosozumab demonstrates potential to address an unmet need in osteoporosis management in Asia. INTRODUCTION: Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. The global ARCH study demonstrated superiority of romosozumab followed by alendronate in reducing fracture risk in high-risk postmenopausal osteoporotic women vs alendronate alone. We report outcomes among ARCH East Asian patients. METHODS: In ARCH, 4093 postmenopausal osteoporotic women with fragility fracture were randomized 1:1 to monthly romosozumab 210 mg or weekly alendronate 70 mg for 12 months, both followed by open-label alendronate. Primary endpoints were incidence of new vertebral fracture (VF) at 24 months and clinical fracture at primary analysis (confirmed fractures in ≥ 330 patients and all patients had opportunity to attend month 24 visit). This post hoc analysis was not powered to detect fracture-rate differences. RESULTS: This analysis included 275 patients from Hong Kong, Korea, and Taiwan. Romosozumab followed by alendronate reduced risk of new VFs at 24 months by 60% (P = 0.11) and clinical fractures at primary analysis by 44% (P = 0.15) vs alendronate alone. Romosozumab followed by alendronate significantly increased mean bone mineral density at 24 months from baseline by a further 9.0%, 3.3%, and 3.0% at the lumbar spine, total hip, and femoral neck vs alendronate alone. Adverse event (AE) rates, including positively adjudicated serious cardiovascular AEs (1.6% vs 1.4% at 12 months for romosozumab vs alendronate), were similar across treatment groups. CONCLUSIONS: Consistent with the global analysis, romosozumab followed by alendronate was associated with lower incidences of new vertebral, clinical, non-vertebral, and hip fractures vs alendronate alone among East Asian patients.

Low free T3 to free T4 ratio was associated with low muscle mass and impaired physical performance in community-dwelling aged population.

In aged population, the association of thyroid hormones on physical performance, especially within their normal range, has yet to be elucidated. In this study, individuals with low serum free T3/free T4 were likely to have low muscle mass and impaired physical performance. PURPOSE: We aimed to evaluate the associations of muscle mass, strength, and physical performance with thyroid hormone in an aged euthyroid population from a community-based cohort. METHODS: We examined 918 men aged over 60 years and 1215 postmenopausal women from the Ansung cohort study. Appendicular skeletal muscle mass divided by square of height (ASM/ht2) was used as the muscle mass index. Hand grip strength was measured using a hydraulic dynamometer. Physical performance was assessed using the short physical performance battery (SPPB). RESULTS: Participants with higher tertiles of free T3 and free T3/free T4 were younger and had higher ASM/ht2, stronger hand grip strength, and higher SPPB scores than those in the lower tertiles. In adjusted models, men within higher tertiles of free T3 had higher ASM/ht2 compared with those within lower tertiles (p = 0.033), whereas subjects with higher tertiles of free T4 had lower ASM/ht2 compared with those within lower tertiles (p = 0.043). Subjects within higher tertiles of free T3/free T4 had higher ASM/ht2 (p < 0.001) and better physical performance (p = 0.048) than those within lower tertiles after adjustments. However, free T3, free T4, or free T3/free T4 was not related to hand grip strength after adjustment for covariates. CONCLUSION: Our results thus indicate that in an aged euthyroid population, low serum free T3/free T4 was a better index for low muscle mass and impaired physical performance than serum free T3 or free T4 alone.

External trigeminal nerve stimulation: Potential rescue treatment for acute vestibular migraine.

OBJECTIVE: Vestibular migraine (VM) is the most common neurologic cause of vertigo among adults. However, there are no specifically studied or approved rescue therapies for acute VM attacks. This study describes how external trigeminal nerve stimulation (eTNS) using the Cefaly® (CEFALY Technology, Seraing, Belgium) device relieves acute VM episodes. METHODS: Single-center, retrospective review of 19 patients with acute VM attacks (seen between May 2018 and June 2019) treated with 20-min eTNS. Prior to treatment, patients graded the severity of their vertigo/headache using a 10-point visual analog scale (VAS) with 0 representing no vertigo/headache, and 10 representing the worst imaginable vertigo/headache. After eTNS, patients graded their vertigo/headache using the same VAS 15 min. In addition, bedside neuro-otologic examination was performed before and after treatment. RESULTS: 19/19 patients reported improvement in vertigo severity. Mean vertigo severity was 6.6 (±2.1; median 7) before eTNS, and 2.7 (±2.6; median 3) following treatment; mean improvement in vertigo was 61.3% (±32.6; median 50.0%). During VM episodes, 14/19 experienced headache. Mean headache severity was 4.8 (±2.4; median 4.5) before eTNS, and was 1.4 (±2.4; median 0) following treatment; mean improvement in headache was 77.2% (±32.7; median 100.0%). Neuro-otologic examination was normal during VM attacks in all except Patient 7 who had spontaneous upbeat nystagmus which resolved after eTNS. Other improvements include improvement of eye pressure, head pressure, and chronic facial pain. No intolerable side effects were reported. CONCLUSION: This study provides preliminary evidence that eTNS is a novel, non-invasive, safe and effective treatment for acute VM attacks.