The Importance of Lassa Fever and Its Disease Management in West Africa.

Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been emphasized as one of the greatest public health threats in West Africa, with up to 300,000 cases and 5000 associated deaths per year. This, and the fact that the disease has been reported in travelers, has driven a rapid production of various vaccine candidates. Several of these vaccines are currently in clinical development, despite limitations in understanding the immune response to infection. Alarmingly, the host immune response has been implicated in the induction of sensorineural hearing loss in LF survivors, legitimately raising safety questions about any future vaccines as well as efficacy in preventing potential hearing loss. The objective of this article is to revisit the importance and prevalence of LF in West Africa, with focus on Nigeria, and discuss current therapeutic approaches and ongoing vaccine development. In addition, we aim to emphasize the need for more scientific studies relating to LF-associated hearing loss, and to promote critical discussion about potential risks and benefits of vaccinating the population in endemic regions of West Africa.

Novel neurodigital interface reduces motion sickness in virtual reality.

Virtual reality (VR) is a computer-created 3D environment with a focus on realistic scenes and pictures created for entertainment, medical and/or educational and training purposes. One of the major side effects of VR immersion reported in the scientific literature, media and social media is Visually Induced Motion Sickness (VIMS), with clinical symptoms such as disorientation, nausea, and oculomotor discomfort. VIMS is mostly caused by the discrepancy between the visual and vestibular systems and can lead to dizziness, nausea, and disorientation. In this study, we present one potential novel solution to combat motion sickness in VR, showcasing a significant reduction of nausea in VR users employing the META Quest 2 headsets in conjunction with a whole-body controller. Using a neurodigital approach, we facilitate a more immersive and comfortable VR experience. Our findings indicate a marked reduction in VR-induced nausea, paving the way to promote VR technology for broader applications across various fields.

Analysis of sensorineural hearing loss in patients attending an otolaryngology clinic in North Central Nigeria.

Hearing loss is the third leading cause of years lived with disability. Approximately 1.4 billion people have hearing loss, of which 80% reside in low- and middle-income countries with limited audiology and otolaryngology care available to them. The objective of this study was to estimate period prevalence of hearing loss and audiogram patterns of patients attending an otolaryngology clinic in North Central Nigeria. A 10-year retrospective cohort study was carried out analyzing 1507 patient records of pure tone audiograms of patients at the otolaryngology clinic at Jos University Teaching Hospital, Plateau State, Nigeria. Prevalence of hearing loss of moderate or higher grade increased significantly and steadily after age 60. Compared to other studies, there was a higher prevalence of overall sensorineural hearing loss (24-28% in our study compared to 1.7-8.4% globally) and higher proportions of the flat audiogram configuration among the younger age patients (40% in younger patients compared to 20% in patients older than 60 years). The higher prevalence of the flat audiogram configuration compared to other parts of the world may be suggestive of an etiology specific to this region, such as the endemic Lassa Fever and Lassa virus infection in addition to cytomegalovirus or other viral infections associated with hearing loss.

Depletion of CD4 and CD8 T Cells Reduces Acute Disease and Is Not Associated with Hearing Loss in ML29-Infected STAT1-/- Mice.

Lassa virus (LASV) is a zoonotic virus endemic to western Africa that can cause a potentially lethal and hemorrhagic disease, Lassa fever (LF). Survivors suffer a myriad of sequelae, most notably sudden onset sensorineural hearing loss (SNHL), the mechanism of which remains unclear. Unfortunately, studies aiming to identify the mechanism of these sequelae are limited due to the biosafety level 4 (BSL4) requirements of LASV itself. ML29, a reassortant virus proposed as an experimental vaccine candidate against LASV, is potentially an ideal surrogate model of LF in STAT1-/- mice due to similar phenotype in these animals. We intended to better characterize ML29 pathogenesis and potential sequelae in this animal model. Our results indicate that while both CD4 and CD8 T cells are responsible for acute disease in ML29 infection, ML29 induces significant hearing loss in a mechanism independent of either CD4 or CD8 T cells. We believe that this model could provide valuable information for viral-associated hearing loss in general.

CD4 T-cell depletion prevents Lassa fever associated hearing loss in the mouse model.

Lassa virus (LASV) is the causative agent of Lassa fever (LF), which presents as a lethal hemorrhagic disease in severe cases. LASV-induced hearing loss in survivors is a huge socioeconomic burden, however, the mechanism(s) leading to hearing loss is unknown. In this study, we evaluate in a mouse LF model the auditory function using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to determine the mechanisms underlying LASV-induced hearing loss. In the process, we pioneered measures of ABR and DPOAE tests in rodents in biosafety level 4 (BSL-4) facilities. Our T cell depletion studies demonstrated that CD4 T-cells play an important role in LASV-induced hearing loss, while CD8 T-cells are critical for the pathogenicity in the acute phase of LASV infection. Results presented in this study may help to develop future countermeasures against acute disease and LASV-induced hearing loss.

Recovery of anosmia in hamsters infected with SARS-CoV-2 is correlated with repair of the olfactory epithelium.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for a pandemic affecting billions of people worldwide. Apart from the extreme global economic impact, the pandemic will likely have a lasting impact through long-term sequelae not yet fully understood. Fully understanding the mechanisms driving the various symptoms and sequelae of SARS-CoV-2 infection will allow for the eventual development of therapeutics to prevent or treat such life-altering symptoms. In this study, we developed a behavioral test of anosmia in SARS-CoV-2-infected hamsters. We find a moderately strong correlation between the level of anosmia and the score of histological damage within the olfactory epithelium. We also find a moderately strong correlation between the level of anosmia and the thickness of the olfactory epithelium, previously demonstrated to be severely damaged upon infection. Thus, this food-searching behavioral test can act as a simple and effective screening method in a hamster model for various therapeutics for SARS-CoV-2-related anosmia.

Sex differences in the auditory functions of rodents.

BACKGROUND: In humans, it is well known that females have better hearing than males. The mechanism of this influence of sex on auditory function in humans is not well understood. Testing the hypothesis of underlying mechanisms often relies on preclinical research, a field in which sex bias still exists unconsciously. Rodents are popular research models in hearing, thus it is crucial to understand the sex differences in these rodent models when studying health and disease in humans. OBJECTIVES: This review aims to summarize the existing sex differences in the auditory functions of rodent species including mouse, rat, Guinea pig, Mongolian gerbil, and chinchilla. In addition, a concise summary of the hearing characteristics and the advantages and the drawbacks of conducting auditory experiments in each rodent species is provided. DESIGNS: Manuscripts were identified in PubMed and Ovid Medline for the queries "Rodent", "Sex Characteristics", and "Hearing or Auditory Function". Manuscripts were included if they were original research, written in English, and use rodents. The content of each manuscript was screened for the sex of the rodents and the discussion of sex-based results. CONCLUSIONS: The sex differences in auditory function of rodents are prevalent and influenced by multiple factors including physiological mechanisms, sex-based anatomical variations, and stimuli from the external environment. Such differences may play a role in understanding and explaining sex differences in hearing of humans and need to be taken into consideration for developing clinical therapies aim to improve auditory performances.

Epidemiological review of confirmed Lassa fever cases during 2016-2018, in Plateau State, North Central Nigeria.

Lassa fever (LF) is endemic in West Africa and constitutes a significant public health concern due to its potential for epidemics and associated high mortality. The first reported case and management of Lassa fever in Plateau State occurred more than 50 years ago. We set out to undertake a three-year epidemiological review of LF cases in Plateau State, North Central Nigeria. This is a retrospective study of all confirmed LF cases in Plateau State between 2016 and 2018. Plateau state Lassa fever- Line list and patient case records were used to extract relevant data. Lassa PCR was carried out at the NCDC accredited Laboratory network. Data analysis was done using STATA version SE14.1. Forty-four persons (44) had confirmed LF over the examined period, 18 (41%) in 2016, 15 (34%) in 2017 and 11 (25%) in 2018. The mean age was 29.7±14.6 years and 53% were males. Sixty-six percent (66%) of the patients resided in rural areas. It affected all local government areas (LGA) in the state except Pankshin, Jos East and Kanke LGAs. Twenty-five percent (25%) of the cases occurred among underprivileged communities of Jos North and another 25% in rural dwellers of Langtang North. Fifty-nine percent (59%) of cases occurred during the 1st quarter, 27% the 2nd quarter and 18% the 3rd quarter of the year. The case fatality rate was 57%. LF is endemic in Plateau State. Prevention strategies must be sustained year round and target the youth, urban and rural underprivileged communities. There is also need for case management improvement to reduce mortality.

Regeneration Profiles of Olfactory Epithelium after SARS-CoV-2 Infection in Golden Syrian Hamsters.

Olfactory dysfunction is one of the most frequent and specific symptoms of coronavirus disease 2019 (COVID-19). Information on the damage and repair of the neuroepithelium and its impact on olfactory function after COVID-19 is still incomplete. While severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the ongoing worldwide outbreak of COVID-19, little is known about the changes triggered by SARS-CoV-2 in the olfactory epithelium (OE) at the cellular level. Here, we report profiles of the OE after SARS-CoV-2 infection in golden Syrian hamsters, which is a reliable animal model of COVID-19. We observed severe damage in the OE as early as 3 days postinoculation and regionally specific damage and regeneration of the OE within the nasal cavity; the nasal septal region demonstrated the fastest recovery compared to other regions in the nasal turbinates. These findings suggest that anosmia related to SARS-CoV-2 infection may be fully reversible.

Auditory function analysis in immunodeficient STAT1 knock-out mice: Considerations for viral infection models.

The STAT1 knock-out (KO) mouse is a frequently used transgenic immunodeficient strain to model human viral and bacterial diseases. The Lassa fever model was established in the STAT1 KO mice mimicking phenotypes seen in human patients including deafness in survivors. This model develops hearing loss at high prevalence and is a valuable tool to investigate viral infection-induced hearing loss. However, Lassa virus is a highly contagious and regulated agent requiring the unique logistics of the biosafety level 4 posing limitations for experimental work. Therefore, we did a detailed auditory analysis of the STAT1 KO mice to assess baseline auditory function in preparation for further auditory behavioral studies. Auditory brainstem response and distortion product otoacoustic emission tests were performed on males and females of the STAT1 KO mice and was compared to 129S6/SvEv wild type (WT) mice. The male WT mice had the best auditory performance and the female WT mice had the worst hearing performance. The male and female STAT1 KO mice had similar auditory performance to each other, which was intermediate between WT males and females. We conclude that both male and female STAT1 KO mice are suitable for studying viral infection-induced hearing loss.

Current small animal models for LASV hearing loss.

Lassa virus (LASV) is endemic in West Africa, causing an estimated 100000-300000 new infections and up to 5000-10000 deaths yearly. There are no vaccines and therapeutics are extremely limited. Typical case fatality rates are ∼1%, although a recent 2018 Nigerian outbreak featured an unprecedented 25.4% case fatality rate. Survivors of infection suffer a lifetime of sequelae with sudden onset sensorineural hearing loss (SNHL) being the most prevalent. The cause of this hearing loss remains unknown, and there is a critical need for further research on its mechanisms and potential therapeutics. The objective of this review is to outline the only currently available small animal model for LASV-induced hearing loss and to identify potential surrogate models.

The role of GABAB receptors in the vestibular oculomotor system in mice.

Systemic administration of a gamma-amino butyric acid type B (GABAB) receptor agonist, baclofen, affects various physiological and psychological processes. To date, the effects on oculomotor system have been well characterized in primates, however those in mice have not been explored. In this study, we investigated the effects of baclofen focusing on vestibular-related eye movements. Two rotational paradigms, i.e. sinusoidal rotation and counter rotation were employed to stimulate semicircular canals and otolith organs in the inner ear. Experimental conditions (dosage, routes and onset of recording) were determined based on the prior studies exploring the behavioral effects of baclofen in mice. With an increase in dosage, both canal and otolith induced ocular responses were gradually affected. There was a clear distinction in the drug sensitivity showing that eye movements derived from direct vestibulo-ocular reflex pathways were relatively unaltered, while the responses through higher-order neural networks in the vestibular system were substantially decreased. These findings were consistent with those observed in primates suggesting a well-conserved role of GABAB receptors in the oculomotor system across frontal-eyed and lateral-eyed animals. We showed here a previously unrecognized effect of baclofen on the vestibular oculomotor function in mice. When interpreting general animal performance under the drug, the potential contribution of altered balance system should be taken into consideration.

Preserved otolith organ function in caspase-3-deficient mice with impaired horizontal semicircular canal function.

Genetically engineered mice are valuable models for elucidation of auditory and vestibular pathology. Our goal was to establish a comprehensive vestibular function testing system in mice using: (1) horizontal angular vestibulo-ocular reflex (hVOR) to evaluate semicircular canal function and (2) otolith-ocular reflex (OOR) to evaluate otolith organ function and to validate the system by characterizing mice with vestibular dysfunction. We used pseudo off-vertical axis rotation to induce an otolith-only stimulus using a custom-made centrifuge. For the OOR, horizontal slow-phase eye velocity and vertical eye position were evaluated as a function of acceleration. Using this system, we characterized hVOR and OOR in the caspase-3 (Casp3) mutant mice. Casp3 (-/-) mice had severely impaired hVOR gain, while Casp3 (+/-) mice had an intermediate response compared to WT mice. Evaluation of OOR revealed that at low-to-mid frequencies and stimulus intensity, Casp3 mutants and WT mice had similar responses. At higher frequencies and stimulus intensity, the Casp3 mutants displayed mildly reduced otolith organ-related responses. These findings suggest that the Casp3 gene is important for the proper function of the semicircular canals but less important for the otolith organ function.

Animal Model of Sensorineural Hearing Loss Associated with Lassa Virus Infection.

UNLABELLED: Approximately one-third of Lassa virus (LASV)-infected patients develop sensorineural hearing loss (SNHL) in the late stages of acute disease or in early convalescence. With 500,000 annual cases of Lassa fever (LF), LASV is a major cause of hearing loss in regions of West Africa where LF is endemic. To date, no animal models exist that depict the human pathology of LF with associated hearing loss. Here, we aimed to develop an animal model to study LASV-induced hearing loss using human isolates from a 2012 Sierra Leone outbreak. We have recently established a murine model for LF that closely mimics many features of human disease. In this model, LASV isolated from a lethal human case was highly virulent, while the virus isolated from a nonlethal case elicited mostly mild disease with moderate mortality. More importantly, both viruses were able to induce SNHL in surviving animals. However, utilization of the nonlethal, human LASV isolate allowed us to consistently produce large numbers of survivors with hearing loss. Surviving mice developed permanent hearing loss associated with mild damage to the cochlear hair cells and, strikingly, significant degeneration of the spiral ganglion cells of the auditory nerve. Therefore, the pathological changes in the inner ear of the mice with SNHL supported the phenotypic loss of hearing and provided further insights into the mechanistic cause of LF-associated hearing loss. IMPORTANCE: Sensorineural hearing loss is a major complication for LF survivors. The development of a small-animal model of LASV infection that replicates hearing loss and the clinical and pathological features of LF will significantly increase knowledge of pathogenesis and vaccine studies. In addition, such a model will permit detailed characterization of the hearing loss mechanism and allow for the development of appropriate diagnostic approaches and medical care for LF patients with hearing impairment.

Phialemonium infection complicating chronic suppurative otitis media.

Phialemonium infection in humans is rare. We report a 7-year-old healthy boy who presented with chronic otorrhea, which persisted despite adequate antibiotic therapy and four preservative tympanomastoidectomy operations. Following 3 years of intermittent topical antibiotic therapy, cultures eventually grew Phialemonium, which necessitated a more extensive operation, combined with systemic/topical anti-fungal agent to achieve clinical cure.

Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes.

Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1(Δ) mice) were deaf and those with a deletion of Tmc2 (Tmc2(Δ) mice) were phenotypically normal, Tmc1(Δ)Tmc2(Δ) mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. Expression of either exogenous TMC1 or TMC2 rescued mechanotransduction in Tmc1(Δ)Tmc2(Δ) mutant hair cells. Our results indicate that TMC1 and TMC2 are necessary for hair cell mechanotransduction and may be integral components of the mechanotransduction complex. Our data also suggest that persistent TMC2 expression in vestibular hair cells may preserve vestibular function in humans with hearing loss caused by TMC1 mutations.

Inner ear dysfunction in caspase-3 deficient mice.

BACKGROUND: Caspase-3 is one of the most downstream enzymes activated in the apoptotic pathway. In caspase-3 deficient mice, loss of cochlear hair cells and spiral ganglion cells coincide closely with hearing loss. In contrast with the auditory system, details of the vestibular phenotype have not been characterized. Here we report the vestibular phenotype and inner ear anatomy in the caspase-3 deficient (Casp3(-/-)) mouse strain. RESULTS: Average ABR thresholds of Casp3(-/-) mice were significantly elevated (P < 0.05) compared to Casp3(+/-) mice and Casp3(+/+) mice at 3 months of age. In DPOAE testing, distortion product 2F1-F2 was significantly decreased (P < 0.05) in Casp3(-/-) mice, whereas Casp3(+/-) and Casp3(+/+) mice showed normal and comparable values to each other. Casp3(-/-) mice were hyperactive and exhibited circling behavior when excited. In lateral canal VOR testing, Casp3(-/-) mice had minimal response to any of the stimuli tested, whereas Casp3(+/-) mice had an intermediate response compared to Casp3(+/+) mice. Inner ear anatomical and histological analysis revealed gross hypomorphism of the vestibular organs, in which the main site was the anterior semicircular canal. Hair cell numbers in the anterior- and lateral crista, and utricle were significantly smaller in Casp3(-/-) mice whereas the Casp3(+/-) and Casp3(+/+) mice had normal hair cell numbers. CONCLUSIONS: These results indicate that caspase-3 is essential for correct functioning of the cochlea as well as normal development and function of the vestibule.

Topology of transmembrane channel-like gene 1 protein.

Mutations of transmembrane channel-like gene 1 (TMC1) cause hearing loss in humans and mice. TMC1 is the founding member of a family of genes encoding proteins of unknown function that are predicted to contain multiple transmembrane domains. The goal of our study was to define the topology of mouse TMC1 expressed heterologously in tissue culture cells. TMC1 was retained in the endoplasmic reticulum (ER) membrane of five tissue culture cell lines that we tested. We used anti-TMC1 and anti-HA antibodies to probe the topologic orientation of three native epitopes and seven HA epitope tags along full-length TMC1 after selective or complete permeabilization of transfected cells with digitonin or Triton X-100, respectively. TMC1 was present within the ER as an integral membrane protein containing six transmembrane domains and cytosolic N- and C-termini. There is a large cytoplasmic loop, between the fourth and fifth transmembrane domains, with two highly conserved hydrophobic regions that might associate with or penetrate, but do not span, the plasma membrane. Our study is the first to demonstrate that TMC1 is a transmembrane protein. The topologic organization revealed by this study shares some features with that of the shaker-TRP superfamily of ion channels.

Otolaryngologic markers for the early diagnosis of Turner syndrome.

OBJECTIVE: To identify and characterize otolaryngologic markers for the early diagnosis of Turner syndrome (TS). STUDY DESIGN: Prospective cohort survey. SETTING: Clinical Center of the National Institutes of Health (NIH). PATIENTS: Ninety-one females, 7-61 years old (average=28.7 y), enrolled in a multidisciplinary study of karyotype-phenotype correlations in TS. MAIN OUTCOME MEASURES: Age at diagnosis, X chromosome karyotype, history of chronic or recurrent otitis media (OM), sensorineural hearing loss (SNHL), palate dysmorphism, pinna deformity, pterygium colli, low posterior hairline, low-set ears, and micrognathia. RESULTS: Sixty-nine (76%) patients had a history of chronic or recurrent OM, 62 (68%) had a dysmorphic palate, 57 (63%) had SNHL, and 90 (99%) had one or more of these findings. 83 (91%; average age at diagnosis=9.4 y) had one or more external craniofacial signs: pinna abnormalities, pterygium colli, low-set ears, micrognathia or a low posterior hairline. Eight patients (average age at diagnosis=13.2 y) had no external craniofacial signs, although seven (88%) of these eight patients had a history of chronic or recurrent OM, dysmorphic palate or SNHL. The age at diagnosis was not significantly different between groups with or without external craniofacial signs (P=0.126). CONCLUSIONS: PATIENTS with mild or incompletely penetrant TS phenotypes often present with otitis media, hearing loss, or both before the diagnosis of TS is established. Palatal dysmorphism, including ogival morphology, is another otolaryngologic marker for TS. Prompt recognition of these manifestations of TS could hasten its diagnosis and appropriate medical care.

Connexin 26 mutation in keratitis-ichthyosis-deafness (KID) syndrome in mother and daughter with combined conductive and sensorineural hearing loss.

BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome most commonly results from a mutation in the gap-junctional protein connexin 26 (Cx26) gene, GJB2. Most cases are sporadic and are associated with sensorineural hearing loss. METHODS: We encountered a mother and daughter with KID syndrome, and pursued genetic analysis and an extensive hearing loss evaluation. RESULTS: The analysis of genomic DNA of both affected patients revealed the mutation 148G --> A in GJB2 (D50N). No mutation was found in an unaffected son. Auditory phenotype analysis showed a combined conductive and sensorineural hearing loss in both affected patients. CONCLUSIONS: This is the second vertical transmission of the D50N mutation. These are the first two cases with combined sensorineural and conductive hearing loss without any significant history of middle ear disease. This points to the possibility that the Cx26 D50N mutation can cause conductive hearing loss.