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SUMMARYWe used the clustered lot quality assurance sampling (clustered-LQAS) technique to identify districts with low immunization coverage and guide mop-up actions during the last 4 days of a combined oral polio vaccine (OPV) and yellow fever (YF) vaccination campaign conducted in Cameroon in May 2009. We monitored 17 pre-selected districts at risk for low coverage. We designed LQAS plans to reject districts with YF vaccination coverage <90% and with OPV coverage <95%. In each lot the sample size was 50 (five clusters of 10) with decision values of 3 for assessing OPV and 7 for YF coverage. We 'rejected' 10 districts for low YF coverage and 14 for low OPV coverage. Hence we recommended a 2-day extension of the campaign. Clustered-LQAS proved to be useful in guiding the campaign vaccination strategy before the completion of the operations. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To guide immunization policy, we determined the public health benefit of introducing Haemophilus influenzae type b (Hib) vaccine in Uganda and estimated the vaccine effectiveness. METHODS: Surveillance data for acute bacterial meningitis among children aged 0-59 months were reviewed from three hospital sentinel sites, for July 2001 to June 2007, to determine the incidence of Hib meningitis, the effectiveness of Hib vaccine with a case-control design, and the number of vaccine-preventable cases and deaths of Hib disease in Uganda. FINDINGS: Of the 13 978 children from 17 districts with suspected bacterial meningitis, 269 had confirmed Hib meningitis, declining from 69 patients in the prevaccine year (2001-2002) to three in 2006-2007. Hib meningitis incidence dropped from 88 cases per 100,000 children aged < 5 years in the year before vaccine introduction to 13 within 4 years, and to near zero in the fifth year. Vaccine effectiveness for 2 or more doses was 93% (95% confidence interval, CI: 69-99) against confirmed Hib meningitis and 53% (95% CI: 11-68) against purulent meningitis of unknown cause. In Uganda, Hib vaccine prevents an estimated 28 000 cases of pneumonia and meningitis, 5000 deaths and 1000 severe meningitis sequelae each year. CONCLUSION: Infant immunization with Hib vaccine has virtually eliminated Hib meningitis in Uganda within 5 years. Ensuring long-term benefits of Hib vaccine urgently requires sustainable vaccine financing, high-quality ongoing surveillance, and a health sector able to deliver a robust immunization programme. Copyright © 2008 World Health Organization [ABSTRACT FROM AUTHOR]

Competing Interests: JBN is supported by the US National Institutes of Health (grant numbers NIH/FIC 1R25TW011217-01, NIH/FIC 1D43TW010937-01A1, NIH/FIC D43TW011827-01A1, NIH/FIC 1R21TW011706-0, and NIH/NIAID 5U01AI096299-13). FN and AZ are codirectors of the Pan-African Network on Emerging and Re-Emerging Infections funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) within the EU Horizon 2020 Framework Programme. FN and AZ also acknowledge support from the EDCTP Central Africa Clinical Research Network. AZ is a UK National Institute for Health Research senior investigator, and a Mahathir Science Award and EU-EDCTP Pascoal Mocumbi Prize laureate. JJM-T holds National Institutes of Health National Institute of Allergy and Infectious Diseases grants (number 75N91019D00024-P00001-759102000025-5). JK is supported by grant funding from the Canadian Institutes of Health Research and International Development Research Centre (grant numbers MRR-184813 and PPE-185821). ELM is supported by the US National Institutes of Health (grant number 1R01AI182082-01). All other authors declare no competing interests. We thank John L Johnson for critical review and helpful advice. The views and conclusions in this Personal View are those of the authors and do not necessarily represent the views of their institutions.

Background: Bithermal caloric irrigation, video head impulse test (vHIT), and rotational testing are commonly used to assess peripheral vestibular function, but the relative clinical utility of each test in differentiating patients with peripheral vestibulopathy is debated., Objectives: To determine whether (1) the combination of two or more vestibular tests enhances diagnostic utility over a single test; (2) abnormal test results on vestibular tests correlate with one another., Methods: Retrospective analysis of data collected from multidisciplinary vestibular clinics at two academic medical centers from 2016 to 2022., Results: 150 patients (54.10 ± 15.09 years, 88 females) were included. No individual test was significantly better at predicting the presence of peripheral vestibular damage ( p  > 0.05). vHIT test results improved significantly when combined with either the caloric test ( p  = 0.007) or rotary chair test ( p  = 0.039). Caloric and rotational testing had high sensitivity (74.65% and 76.06%, respectively) and specificity (83.54% and 78.48%, respectively). vHIT demonstrated excellent specificity (89.87%) but poor sensitivity (47.89%). Caloric, vHIT, and rotary chair tests results did not correlate with one another ( p  > 0.05)., Conclusions: Vestibular function tests have comparable diagnostic utility, yet each offers unique advantages. Caloric and rotational testing may be best suited for screening peripheral damage and vHIT may function ideally as a confirmatory test., Competing Interests: The authors have no conflicts of interest to disclose., (© [copyright 2023] PLA General Hospital Department of Otolaryngology Head and Neck Surgery. Production and hosting by Elsevier (Singapore) Pte Ltd.)

Vestibular information is available to the brain during navigation, as are the other self-generated (idiothetic) and external (allothetic) sensorimotor cues that contribute to central estimates of position and motion. Rodent studies provide strong evidence that vestibular information contributes to navigation but human studies have been less conclusive. Furthermore, sex-based differences have been described in human navigation studies performed with the head stationary, a situation where dynamic vestibular (and other idiothetic) information is absent, but sex differences in the utilization of vestibular information have not been described. Here, we studied men and women with severe bilateral vestibular damage as they navigated through a visually barren virtual reality environment and compared their performance to normal men and women. Two navigation protocols were employed, which either activated dynamic idiothetic cues ('dynamic task', navigate by turning, walking in place) or eliminated them ('static task', navigate with key presses, head stationary). For both protocols, we employed a standard 'triangle completion task' in which subjects moved to two visual targets in series and then were required to return to their perceived starting position without localizing visual information. The angular and linear 'accuracy' (derived from response error) and 'precision' (derived from response variability) were calculated. Comparing performance 'within tasks', navigation on the dynamic paradigm was worse in male vestibular-deficient patients than in normal men but vestibular-deficient and normal women were equivalent; on the static paradigm, vestibular-deficient men (but not women) performed better than normal subjects. Comparing performance 'between tasks', normal men performed better on the dynamic than the static paradigm while vestibular-deficient men and both normal and vestibular-deficient women were equivalent on both tasks. Statistical analysis demonstrated that for the angular precision metric, sex had a significant effect on the interaction between vestibular status and the test paradigm. These results provide evidence that humans use vestibular information when they navigate in a virtual visual environment and that men and women may utilize vestibular (and visual) information differently. On our navigation paradigm, men used vestibular information to improve navigation performance, and in the presence of severe vestibular damage, they utilized visual information more effectively. In contrast, we did not find evidence that women used vestibular information while navigating on our virtual task, nor did we find evidence that they improved their utilization of visual information in the presence of severe vestibular damage., Competing Interests: The authors report no competing interests., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

The 2022-2023 mpox outbreak predominantly affected adult men; 1.3% of reported cases were in children and adolescents <18 years of age. Analysis of global surveillance data showed 1 hospital intensive care unit admission and 0 deaths in that age group. Transmission routes and clinical manifestations varied across age subgroups.

Patients with bilateral vestibulopathy suffer from a variety of complaints, leading to a high individual and social burden. Available treatments aim to alleviate the impact of this loss and improve compensatory strategies. Early experiments with electrical stimulation of the vestibular nerve in combination with knowledge gained by cochlear implant research, have inspired the development of a vestibular neuroprosthesis that can provide the missing vestibular input. The feasibility of this concept was first demonstrated in animals and later in humans. Currently, several research groups around the world are investigating prototype vestibular implants, in the form of vestibular implants as well as combined cochlear and vestibular implants. The aim of this review is to convey the presentations and discussions from the identically named symposium that was held during the 2021 MidWinter Meeting of the Association for Research in Otolaryngology, with researchers involved in the development of vestibular implants targeting the ampullary nerves. Substantial advancements in the development have been made. Yet, research and development processes face several challenges to improve this neuroprosthesis. These include, but are not limited to, optimization of the electrical stimulation profile, refining the surgical implantation procedure, preserving residual labyrinthine functions including hearing, as well as gaining regulatory approval and establishing a clinical care infrastructure similar to what exists for cochlear implants. It is believed by the authors that overcoming these challenges will accelerate the development and increase the impact of a clinically applicable vestibular implant., (© 2023. The Author(s).)

Background: In May 2022, several countries with no history of sustained community transmission of mpox (formerly known as monkeypox) notified WHO of new mpox cases. These cases were soon followed by a large-scale outbreak, which unfolded across the world, driven by local, in-country transmission within previously unaffected countries. On July 23, 2022, WHO declared the outbreak a Public Health Emergency of International Concern. Here, we aim to describe the main epidemiological features of this outbreak, the largest reported to date., Methods: In this analysis of global surveillance data we analysed data for all confirmed mpox cases reported by WHO Member States through the global surveillance system from Jan 1, 2022, to Jan 29, 2023. Data included daily aggregated numbers of mpox cases by country and a case reporting form (CRF) containing information on demographics, clinical presentation, epidemiological exposure factors, and laboratory testing. We used the data to (1) describe the key epidemiological and clinical features of cases; (2) analyse risk factors for hospitalisation (by multivariable mixed-effects binary logistic regression); and (3) retrospectively analyse transmission trends. Sequencing data from GISAID and GenBank were used to analyse monkeypox virus (MPXV) genetic diversity., Findings: Data from 82 807 cases with submitted CRFs were included in the analysis. Cases were primarily due to clade IIb MPXV (mainly lineage B.1, followed by lineage A.2). The outbreak was driven by transmission among males (73 560 [96·4%] of 76 293 cases) who self-identify as men who have sex with men (25 938 [86·9%] of 29 854 cases). The most common reported route of transmission was sexual contact (14 941 [68·7%] of 21 749). 3927 (7·3%) of 54 117 cases were hospitalised, with increased odds for those aged younger than 5 years (adjusted odds ratio 2·12 [95% CI 1·32-3·40], p=0·0020), aged 65 years and older (1·54 [1·05-2·25], p=0·026), female cases (1·61 [1·35-1·91], p<0·0001), and for cases who are immunosuppressed either due to being HIV positive and immunosuppressed (2·00 [1·68-2·37], p<0·0001), or other immunocompromising conditions (3·47 [1·84-6·54], p=0·0001)., Interpretation: Continued global surveillance allowed WHO to monitor the epidemic, identify risk factors, and inform the public health response. The outbreak can be attributed to clade IIb MPXV spread by newly described modes of transmission., Funding: WHO Contingency Fund for Emergencies., Translations: For the French and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interest., (This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Maintaining balance involves the combination of sensory signals from the visual, vestibular, proprioceptive, and auditory systems. However, physical and biological constraints ensure that these signals are perceived slightly asynchronously. The brain only recognizes them as simultaneous when they occur within a period of time called the temporal binding window (TBW). Aging can prolong the TBW, leading to temporal uncertainty during multisensory integration. This effect might contribute to imbalance in the elderly but has not been examined with respect to vestibular inputs. Here, we compared the vestibular-related TBW in 13 younger and 12 older subjects undergoing 0.5 Hz sinusoidal rotations about the earth-vertical axis. An alternating dichotic auditory stimulus was presented at the same frequency but with the phase varied to determine the temporal range over which the two stimuli were perceived as simultaneous at least 75% of the time, defined as the TBW. The mean TBW among younger subjects was 286 ms (SEM ± 56 ms) and among older subjects was 560 ms (SEM ± 52 ms). TBW was related to vestibular sensitivity among younger but not older subjects, suggesting that a prolonged TBW could be a mechanism for imbalance in the elderly person independent of changes in peripheral vestibular function., Competing Interests: CONFLICTS OF INTEREST None of the authors have conflicts to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Neurofibromatosis type 2-related schwannomatosis is a genetic disorder characterized by neurologic tumours, most typically vestibular schwannomas that originate on the vestibulo-cochlear nerve(s). Although vestibular symptoms can be disabling, vestibular function has never been carefully analysed in neurofibromatosis type 2-related schwannomatosis. Furthermore, chemotherapy (e.g. bevacizumab) can reduce tumour volume and improve hearing in neurofibromatosis type 2-related schwannomatosis, but nothing is known about its vestibular effects. In this report, we studied the three primary vestibular-mediated behaviours (eye movements, motion perception and balance), clinical vestibular disability (dizziness and ataxia), and imaging and hearing in eight untreated patients with neurofibromatosis type 2-related schwannomatosis and compared their results with normal subjects and patients with sporadic, unilateral vestibular schwannoma tumours. We also examined how bevacizumab affected two patients with neurofibromatosis type 2-related schwannomatosis. Vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis degraded vestibular precision (inverse of variability, reflecting a reduced central signal-to-noise ratio) but not vestibular accuracy (amplitude relative to ideal amplitude, reflecting the central signal magnitude) and caused clinical disability. Bevacizumab improved vestibular precision and clinical disability in both patients with neurofibromatosis type 2-related schwannomatosis but did not affect vestibular accuracy. These results demonstrate that vestibular schwannoma tumours in our neurofibromatosis type 2-related schwannomatosis population degrade the central vestibular signal-to-noise ratio, while bevacizumab improves the signal-to-noise ratio, changes that can be explained mechanistically by the addition (schwannoma) and suppression (bevacizumab) of afferent neural noise., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Competing Interests: EJL was supported by the US National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number U24AI162625. All other authors declare no competing interests. The working group thanks African scientists who advocated for new clade names for MPXV, and front-line health workers and advocates at Rézo, a Montreal community based organisation for gay, bisexual, queer, cis, and trans men who have sex with men, who led a grassroots movement to rename mpox. DU chaired the ad-hoc experts meeting on MPXV clades and variants, which involved authors AA, JB, KK, EJL, MRM, TdO, JO, AR, and RFL, and experts Ifedayo Adetifa, Oluwatoni Akinola, Olajumoke Babatunde, Sylvie Briand, Clarissa Damaso, Inger Damon, Drew Endy, Delia Enria, Mariano Esteban, Bradley Hersh, Christina Hutson, Yu Li, Abdi Mahamud, Sandy Mak, Peter Mala, Colin McInnes, Jean-Vivien Mombouli, Richard Neher, Nnaemeka Ndodo, Mark Perkins, Mike Ryan, Jilian Sacks, Soumya Swaminathan, Henda Triki. We thank Meng Zhang, Co-Chair of the ICD Classification and Statistics Advisory Committee, all participants in these discussions, and Maria Van Kerkhove for ongoing support. The findings and conclusions in this Comment are those of the authors and do not necessarily represent the views of their respective institutions.

Objective: To characterize visuospatial and nonvisuospatial cognitive domains affected by vestibular loss and determine whether patient-reported outcomes measures (PROMs) correlate with performance on neuropsychological tests., Study Design: Cross-sectional study., Setting: University-based tertiary medical center., Patients: Sixty-nine age-matched subjects: 25 patients with bilateral vestibular loss (BVL), 14 patients with unilateral vestibular loss (UVL), and 30 normal controls (NC)., Interventions: Neuropsychological tests used to assess visuospatial and auditory short-term and working memory, number magnitude representation, executive function, and attention. Validated PROMs used to evaluate quality of life and subjective cognitive impairment., Main Outcome Measures: Performance on neuropsychological tests and scores on PROM surveys., Results: BVL and UVL patients performed significantly worse than NC subjects on tasks requiring visuospatial representation compared with NC subjects ( p < 0.01). BVL patients demonstrated decreased performance on spatial representation tasks compared with UVL and NC subjects ( p < 0.05 and p < 0.05, respectively). All subject groups performed similarly on tasks assessing nonvisuospatial cognitive domains, such as auditory short-term and working memory, executive function, and attention. PROMs did not seem to correlate with performance on neuropsychological tasks., Conclusion: Patients with vestibular loss exhibit impairments in tasks requiring visuospatial representation but perform similarly to NC subjects in tasks of auditory working memory, executive function, or attention. Currently available questionnaires may be insufficient to screen patients for cognitive deficits., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

Objective:  Extensive animal research has shown that vestibular damage can be associated with cognitive deficits. More recently, new evidence has emerged linking vestibular disorders to cognitive impairment in humans. Herein, we review contemporary research on the pathophysiology of cognitive-vestibular interactions and discuss its emerging clinical relevance., Data Sources: PubMed, Embase, and Cochrane databases., Review Methods: A systematic literature search was performed with combinations of search terms: "cognition," "cognitive impairment," "chronic fatigue," "brain fog," "spatial navigation," "attention," "memory," "executive function," "processing speed," and "vestibular hypofunction." Relevant articles were considered for inclusion, including basic and clinical studies, case series, and major reviews., Conclusions: Patients with vestibular disorders can demonstrate long-term deficits in both spatial and nonspatial cognitive domains. The underlying mechanism(s) linking the vestibular system to cognitive function is not well characterized, but several neuro-biologic correlates have been identified. Additional screening tools are required to identify individuals at risk for cognitive impairment, and further research is needed to determine whether treatment of vestibular dysfunction has the capacity to improve cognitive function., Implications for Practice: Physicians should be aware of emerging data supporting the presence of cognitive deficits in patients with vestibular disorders. Prevention and treatment of long-term cognitive deficits may be possible through screening and rehabilitation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Velocity storage is a centrally-mediated mechanism that processes peripheral vestibular inputs. One prominent aspect of velocity storage is its effect on dynamic responses to yaw rotation. Specifically, when normal human subjects are accelerated to constant angular yaw velocity, horizontal eye movements and perceived angular velocity decay exponentially with a time constant circa 15-30 s, even though the input from the vestibular periphery decays much faster (~ 6 s). Peripheral vestibular damage causes a time constant reduction, which is useful for clinical diagnoses, but a mechanistic explanation for the relationship between vestibular damage and changes in these behavioral dynamics is lacking. It has been hypothesized that Bayesian optimization determines ideal velocity storage dynamics based on statistics of vestibular noise and experienced motion. Specifically, while a longer time constant would make the central estimate of angular head velocity closer to actual head motion, it may also result in the accumulation of neural noise which simultaneously degrades precision. Thus, the brain may balance these two effects by determining the time constant that optimizes behavior. We applied a Bayesian optimal Kalman filter to determine the ideal velocity storage time constant for unilateral damage. Predicted time constants were substantially lower than normal and similar to patients. Building on our past work showing that Bayesian optimization explains age-related changes in velocity storage, we also modeled interactions between age-related hair cell loss and peripheral damage. These results provide a plausible mechanistic explanation for changes in velocity storage after peripheral damage. Results also suggested that even after peripheral damage, noise originating in the periphery or early central processing may remain relevant in neurocomputations. Overall, our findings support the hypothesis that the brain optimizes velocity storage based on the vestibular signal-to-noise ratio., (© 2022. The Author(s) under exclusive licence to Association for Research in Otolaryngology.)

Background: Falls are the leading cause of fatal and nonfatal injuries among adults over 65 years old. The increase in fall mortality rates is likely multifactorial. With a lack of key drivers identified to explain rising rates of death from falls, accurate predictive modelling can be challenging, hindering evidence-based health resource and policy efforts. The objective of this work is to examine the predictive power of geographic utilization and longitudinal trends in mortality from unintentional falls amongst different demographic and geographic strata., Methods: This is a nationwide, retrospective cohort study using the United States Centers for Disease Control (CDC) Web-based Injury Statistics Query and Reporting System (WISQARS) database. The exposure was death from an unintentional fall as determined by the CDC. Outcomes included aggregate and trend crude and age-adjusted death rates. Health care utilization, reimbursement, and cost metrics were also compared., Results: Over 2001 to 2018, 465,486 total deaths due to unintentional falls were recorded with crude and age-adjusted rates of 8.42 and 7.76 per 100,000 population respectively. Comparing age-adjusted rates, males had a significantly higher age-adjusted death rate (9.89 vs. 6.17; p <  0.00001), but both male and female annual age-adjusted mortality rates are expected to rise (Male: + 0.25 rate/year, R 2 = 0.98; Female: + 0.22 rate/year, R 2 = 0.99). There were significant increases in death rates commensurate with increasing age, with the adults aged 85 years or older having the highest aggregate (201.1 per 100,000) and trending death rates (+ 8.75 deaths per 100,000/year, R 2 = 0.99). Machine learning algorithms using health care utilization data were accurate in predicting geographic age-adjusted death rates., Conclusions: Machine learning models have high accuracy in predicting geographic age-adjusted mortality rates from health care utilization data. In the United States from 2001 through 2018, adults aged 85+ years carried the highest death rate from unintentional falls and this rate is forecasted to accelerate., (© 2022. The Author(s).)

Imbalance and dizziness are disabling symptoms for many patients with vestibular schwannomas (VS) but symptom severity typically does not correlate with the vestibulo-ocular reflex (VOR) amplitude-based metrics used to assess peripheral vestibular damage. In this study, we tested the hypothesis that imbalance and dizziness in patients with VS relate to VOR metrics that are not based on response amplitude. Twenty-four patients with unilateral, sporadic VS tumors were studied, and objective (balance) and subjective (dizziness) vestibular dysfunction was quantified. The VOR was tested using two yaw-axis motion stimuli, low-frequency en-bloc sinusoidal, and high-frequency head-on-body impulsive rotations. Imbalance correlated with VOR precision (the inverse of the trial-to-trial variability) and with low-frequency VOR dynamics (quantified with the time constant), and these two metrics were also strongly correlated. Dizziness correlated with the VOR bias caused by an imbalance in static central vestibular tone, but not with dynamic VOR metrics. VOR accuracy (mean response amplitude relative to the ideal response) was not correlated with the severity of imbalance or dizziness or with measures of VOR precision or time constant. Imbalance in patients with VS, therefore, scales with VOR precision and time constant, both of which appear to reflect the central vestibular signal-to-noise ratio, but not with VOR slow-phase accuracy, which is based on the magnitude of the central vestibular signals. Dizziness was related to the presence of a static central tone imbalance but not to any VOR metrics, suggesting that abnormal perception in VS may be affected by factors that are not captured by yaw-axis VOR measurements. NEW & NOTEWORTHY The severity of symptoms associated with unilateral vestibular schwannomas (VS) is poorly correlated with standard yaw-axis vestibulo-ocular reflex (VOR) metrics that are based on response amplitude. In this study, we show that the balance and perceptual dysfunction experienced by patients with VS scales with VOR metrics that capture information about the central signal-to-noise ratio (balance) and central static tone (dizziness), but are not correlated with the VOR gain, which reflects central signal amplitude.

Background: Gait and balance difficulties are among the most common clinical manifestations in adults with X-linked adrenoleukodystrophy, but little is known about the contributions of sensory loss, motor dysfunction, and postural control to gait dysfunction and fall risk. Objective: To quantify gait and balance deficits in both males and females with adrenoleukodystrophy and evaluate how environmental perturbations (moving surfaces and visual surrounds) affect balance and fall risk. Methods: We assessed sensory and motor contributions to gait and postural instability in 44 adult patients with adrenoleukodystrophy and 17 healthy controls using three different functional gait assessments (25 Foot Walk test, Timed Up and Go, and 6 Minute Walk test) and computerized dynamic posturography. Results: The median Expanded Disability Status Scale score for the patient cohort was 3.0 (range 0.0-6.5). Both males and females with adrenoleukodystrophy showed impairments on all three functional gait assessments relative to controls ( P < 0.001). Performance on walking tests and Expanded Disability Status Scale scores correlated with incidence of falls on computerized dynamic posturography, with the 25 Foot Walk being a moderately reliable predictor of fall risk (area under the ROC curve = 0.7675, P = 0.0038). Conclusion: We demonstrate that gait difficulties and postural control deficits occur in patients with adrenoleukodystrophy, albeit at an older age in females. Postural deficits were aggravated by eyes closed and dynamic conditions that rely on vestibular input, revealing challenges to the interplay of motor, sensory and vestibular circuitry in adrenoleukodystrophy., Competing Interests: FE reports sponsored research contracts with Minoryx Therapeutics and consultancies with Autobahn Therapeutics, Minoryx Therapeutics, and SwanBio Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Godbole, Sadjadi, DeBono, Grant, Kelly, James, Stephen, Balkwill, Lewis and Eichler.)

Gravity is a pervasive environmental stimulus, and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or vestibular implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal VI-mediated angular head velocity information, but it remains unknown whether a canal VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity. Here, we tested the hypothesis that a canal VI that transduces angular head velocity and provides this information to the brain via motion-modulated electrical stimulation of canal afferent nerves could improve the perception of angular head position relative to gravity in monkeys with severe vestibular damage. Using a subjective visual vertical task, we found that normal female monkeys accurately sensed the orientation of the head relative to gravity during dynamic tilts, that this ability was degraded following bilateral vestibular damage, and improved when the canal VI was used. These results demonstrate that a canal VI can improve graviception in vestibulopathic animals, suggesting that it could reduce the disabling perceptual and postural deficits experienced by patients with severe vestibular damage. SIGNIFICANCE STATEMENT Patients with vestibular damage experience impaired vision, spatial perception, and balance, symptoms that could potentially respond to a vestibular implant (VI). Anatomic features facilitate semicircular canal (angular velocity) prosthetics but inhibit approaches with the otolith (linear acceleration) organs, and canal VIs that sense angular head velocity can generate compensatory eye velocity responses in vestibulopathic subjects. Can the brain use canal VI head velocity information to improve estimates of head orientation (e.g., head position relative to gravity), which is a prerequisite for accurate spatial perception and posture? Here we show that a canal VI can improve the perception of head orientation in vestibulopathic monkeys, results that are highly significant because they suggest that VIs mimicking canal function can improve spatial orientation and balance in vestibulopathic patients., (Copyright © 2021 the authors.)

The vestibular system is vital for maintaining balance and stabilizing gaze and vestibular damage causes impaired postural and gaze control. Here we examined the effects of vestibular loss and subsequent compensation on head motion kinematics during voluntary behavior. Head movements were measured in vestibular schwannoma patients before, and then 6 weeks and 6 months after surgical tumor removal, requiring sectioning of the involved vestibular nerve (vestibular neurectomy). Head movements were recorded in six dimensions using a small head-mounted sensor while patients performed the Functional Gait Assessment (FGA). Kinematic measures differed between patients (at all three time points) and normal subjects on several challenging FGA tasks, indicating that vestibular damage (caused by the tumor or neurectomy) alters head movements in a manner that is not normalized by central compensation. Kinematics measured at different time points relative to vestibular neurectomy differed substantially between pre-operative and 6-week post-operative states but changed little between 6-week and > 6-month post-operative states, demonstrating that compensation affecting head kinematics is relatively rapid. Our results indicate that quantifying head kinematics during self-generated gait tasks provides valuable information about vestibular damage and compensation, suggesting that early changes in patient head motion strategy may be maladaptive for long-term vestibular compensation.

Rapid diagnostics, vaccines and therapeutics are important interventions for the management of the 2019 novel coronavirus (2019-nCoV) outbreak. It is timely to systematically review the potential of these interventions, including those for Middle East respiratory syndrome-Coronavirus (MERS-CoV) and severe acute respiratory syndrome (SARS)-CoV, to guide policymakers globally on their prioritization of resources for research and development. A systematic search was carried out in three major electronic databases (PubMed, Embase and Cochrane Library) to identify published studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Supplementary strategies through Google Search and personal communications were used. A total of 27 studies fulfilled the criteria for review. Several laboratory protocols for confirmation of suspected 2019-nCoV cases using real-time reverse transcription polymerase chain reaction (RT-PCR) have been published. A commercial RT-PCR kit developed by the Beijing Genomic Institute is currently widely used in China and likely in Asia. However, serological assays as well as point-of-care testing kits have not been developed but are likely in the near future. Several vaccine candidates are in the pipeline. The likely earliest Phase 1 vaccine trial is a synthetic DNA-based candidate. A number of novel compounds as well as therapeutics licensed for other conditions appear to have in vitro efficacy against the 2019-nCoV. Some are being tested in clinical trials against MERS-CoV and SARS-CoV, while others have been listed for clinical trials against 2019-nCoV. However, there are currently no effective specific antivirals or drug combinations supported by high-level evidence., Competing Interests: The authors declare no conflict of interest.

Vestibular migraine (VM) is the most common cause of spontaneous vertigo but remains poorly understood. We investigated the hypothesis that central vestibular pathways are sensitized in VM by measuring self-motion perceptual thresholds in patients and control subjects and by characterizing the vestibulo-ocular reflex (VOR) and vestibular and headache symptom severity. VM patients were abnormally sensitive to roll tilt, which co-modulates semicircular canal and otolith organ activity, but not to motions that activate the canals or otolith organs in isolation, implying sensitization of canal-otolith integration. When tilt thresholds were considered together with vestibular symptom severity or VOR dynamics, VM patients segregated into two clusters. Thresholds in one cluster correlated positively with symptoms and with the VOR time constant; thresholds in the second cluster were uniformly low and independent of symptoms and the time constant. The VM threshold abnormality showed a frequency-dependence that paralleled the brain stem velocity storage mechanism. These results support a pathogenic model where vestibular symptoms emanate from the vestibular nuclei, which are sensitized by migraine-related brainstem regions and simultaneously suppressed by inhibitory feedback from the cerebellar nodulus and uvula, the site of canal-otolith integration. This conceptual framework elucidates VM pathophysiology and could potentially facilitate its diagnosis and treatment.

A single event can generate asynchronous sensory cues due to variable encoding, transmission, and processing delays. To be interpreted as being associated in time, these cues must occur within a limited time window, referred to as a "temporal binding window" (TBW). We investigated the hypothesis that vestibular deficits could disrupt temporal visual-vestibular integration by determining the relationships between vestibular threshold and TBW in participants with normal vestibular function and with vestibular hypofunction. Vestibular perceptual thresholds to yaw rotation were characterized and compared with the TBWs obtained from participants who judged whether a suprathreshold rotation occurred before or after a brief visual stimulus. Vestibular thresholds ranged from 0.7 to 16.5 deg/s and TBWs ranged from 13.8 to 395 ms. Among all participants, TBW and vestibular thresholds were well correlated ( R 2  = 0.674, P < 0.001), with vestibular-deficient patients having higher thresholds and wider TBWs. Participants reported that the rotation onset needed to lead the light flash by an average of 80 ms for the visual and vestibular cues to be perceived as occurring simultaneously. The wide TBWs in vestibular-deficient participants compared with normal functioning participants indicate that peripheral sensory loss can lead to abnormal multisensory integration. A reduced ability to temporally combine sensory cues appropriately may provide a novel explanation for some symptoms reported by patients with vestibular deficits. Even among normal functioning participants, a high correlation between TBW and vestibular thresholds was observed, suggesting that these perceptual measurements are sensitive to small differences in vestibular function. NEW & NOTEWORTHY While spatial visual-vestibular integration has been well characterized, the temporal integration of these cues is not well understood. The relationship between sensitivity to whole body rotation and duration of the temporal window of visual-vestibular integration was examined using psychophysical techniques. These parameters were highly correlated for those with normal vestibular function and for patients with vestibular hypofunction. Reduced temporal integration performance in patients with vestibular hypofunction may explain some symptoms associated with vestibular loss.

The brain uses information from different sensory systems to guide motor behavior, and aging is associated with simultaneous decline in the quality of sensory information provided to the brain and deterioration in motor control. Correlations between age-dependent decline in sensory anatomical structures and behavior have been demonstrated in many sensorimotor systems, and it has recently been suggested that a Bayesian framework could explain these relationships. Here we show that age-dependent changes in a human sensorimotor reflex, the vestibuloocular reflex, are explained by a Bayesian optimal adaptation in the brain occurring in response to death of motion-sensing hair cells. Specifically, we found that the temporal dynamics of the reflex as a function of age emerge from ( r = 0.93, P < 0.001) a Kalman filter model that determines the optimal behavioral output when the sensory signal-to-noise characteristics are degraded by death of the transducers. These findings demonstrate that the aging brain is capable of generating the ideal and statistically optimal behavioral response when provided with deteriorating sensory information. While the Bayesian framework has been shown to be a general neural principle for multimodal sensory integration and dynamic sensory estimation, these findings provide evidence of longitudinal Bayesian processing over the human life span. These results illuminate how the aging brain strives to optimize motor behavior when faced with deterioration in the peripheral and central nervous systems and have implications in the field of vestibular and balance disorders, as they will likely provide guidance for physical therapy and for prosthetic aids that aim to reduce falls in the elderly. NEW & NOTEWORTHY We showed that age-dependent changes in the vestibuloocular reflex are explained by a Bayesian optimal adaptation in the brain that occurs in response to age-dependent sensory anatomical changes. This demonstrates that the brain can longitudinally respond to age-related sensory loss in an ideal and statistically optimal way. This has implications for understanding and treating vestibular disorders caused by aging and provides insight into the structure-function relationship during aging.

Quantitative animal models are critically needed to provide proof of concept for the investigation of rehabilitative balance therapies (e.g., invasive vestibular prostheses) and treatment response prior to, or in conjunction with, human clinical trials. This paper describes a novel approach to modeling the nonhuman primate postural control system. Our observation that rhesus macaques and humans have even remotely similar postural control motivates the further application of the rhesus macaque as a model for studying the effects of vestibular dysfunction, as well as vestibular prosthesis-assisted states, on human postural control. Previously, system identification methodologies and models were only used to describe human posture. However, here we utilized pseudorandom, roll-tilt balance platform stimuli to perturb the posture of a rhesus monkey in normal and mild vestibular (equilibrium) loss states. The relationship between rhesus monkey trunk sway and platform roll-tilt was determined via stimulus-response curves and transfer function results. A feedback controller model was then used to explore sensory reweighting (i.e., changes in sensory reliance), which prevented the animal from falling off of the tilting platform. Conclusions involving sensory reweighting in the nonhuman primate for a normal sensory state and a state of mild vestibular loss led to meaningful insights. This first-phase effort to model the balance control system in nonhuman primates is essential for future investigations toward the effects of invasive rehabilitative (balance) technologies on postural control in primates, and ultimately, humans.

The purpose of this study was to investigate the effects of various levels of vestibular function on balance in two, free-standing rhesus monkeys. We hypothesized that postural control strategy depended on the severity of vestibular damage. More specifically, that increased muscle stiffness (via short-latency mechanisms) was adequate to compensate for mild damage, but long-latency mechanisms must be utilized for more severe vestibular damage. One animal was studied for pre-ablated and mild vestibular dysfunction states, while a second animal was studied in a pre-ablated and severe vestibular dysfunction state. The vestibulo-ocular reflex (VOR), an eye movement reflex directly linked to vestibular function, was used to quantify the level of vestibular damage. A postural feedback controller model, previously only used for human studies, was modified to interpret non-human primate postural responses (differences observed in the measured trunk roll) for these three levels of vestibular function. By implementing a feedback controller model, we were able to further interpret our empirical findings and model results were consistent with our above hypothesis. This study establishes a baseline for future studies of non-human primate posture.

Damage to the peripheral vestibular system can result in debilitating postural, perceptual, and visual symptoms. A potential new treatment for this clinical problem is to replace some aspects of peripheral vestibular function with an implant that senses head motion and provides this information to the brain by stimulating branches of the vestibular nerve. In this review I consider animal studies performed at our institution over the past 15 years, which have helped elucidate how the brain processes information provided by a vestibular (semicircular canal) implant and how this information could be used to improve the problems experienced by patients with peripheral vestibular damage., (Copyright © 2016 the American Physiological Society.)

In our study, we examined postural stability during head turns for two rhesus monkeys: one animal study contrasted normal and mild bilateral vestibular ablation and a second animal study contrasted severe bilateral vestibular ablation with and without prosthetic stimulation. The monkeys freely stood, unrestrained on a balance platform and made voluntary head turns between visual targets. To quantify each animals' posture, motions of the head and trunk, as well as torque about the body's center of mass, were measured. In the mildly ablated animal, we observed less foretrunk sway in comparison with the normal state. When the canal prosthesis provided electric stimulation to the severely ablated animal, it showed a decrease in trunk sway during head turns. Because the rhesus monkey with severe bilateral vestibular loss exhibited a decrease in trunk sway when receiving vestibular prosthetic stimulation, we propose that the prosthetic electrical stimulation partially restored head velocity information. Our results provide an indication that a semicircular canal prosthesis may be an effective way to improve postural stability in patients with severe peripheral vestibular dysfunction.

Migraine is associated with enhanced motion sickness susceptibility and can cause episodic vertigo [vestibular migraine (VM)], but the mechanisms relating migraine to these vestibular symptoms remain uncertain. We tested the hypothesis that the central integration of rotational cues (from the semicircular canals) and gravitational cues (from the otolith organs) is abnormal in migraine patients. A postrotational tilt paradigm generated a conflict between canal cues (which indicate the head is rotating) and otolith cues (which indicate the head is tilted and stationary), and eye movements were measured to quantify two behaviors that are thought to minimize this conflict: suppression and reorientation of the central angular velocity signal, evidenced by attenuation ("dumping") of the vestibuloocular reflex and shifting of the rotational axis of the vestibuloocular reflex toward the earth vertical. We found that normal and migraine subjects, but not VM patients, displayed an inverse correlation between the extent of dumping and the size of the axis shift such that the net "conflict resolution" mediated through these two mechanisms approached an optimal value and that the residual sensory conflict in VM patients (but not migraine or normal subjects) correlated with motion sickness susceptibility. Our findings suggest that the brain normally controls the dynamic and spatial characteristics of central vestibular signals to minimize intravestibular sensory conflict and that this process is disrupted in VM, which may be responsible for the enhance motion intolerance and episodic vertigo that characterize this disorder., (Copyright © 2016 the American Physiological Society.)

Vestibular migraine (VM), defined as vestibular symptoms caused by migraine mechanisms, is very common but poorly understood. Because dizziness is often provoked in VM patients when the semicircular canals and otolith organs are stimulated concurrently (e.g., tilting the head relative to gravity), we measured tilt perception and eye movements in patients with VM and in migraine and normal control subjects during fixed-radius centrifugation, a paradigm that simultaneously modulates afferent signals from the semicircular canals and otoliths organs. Twenty-four patients (8 in each category) were tested with a motion paradigm that generated an inter-aural centrifugal force of 0.36 G, resulting in a 20° tilt of the gravito-inertial force in the roll plane. We found that percepts of roll tilt developed slower in VM patients than in the two control groups, but that eye movement responses, including the shift in the eye's rotational axis, were equivalent in all three groups. These results demonstrate a change in vestibular perception in VM that is unaccompanied by changes in vestibular-mediated eye movements and suggest that either the brain's integration of canal and otolith signals or the dynamics of otolith responses are aberrant in patients with VM.

The cerebellum was historically considered a brain region dedicated to motor control, but it has become clear that it also contributes to sensory processing, particularly when sensory discrimination is required. Prior work, for example, has demonstrated a cerebellar contribution to sensory discrimination in the visual and auditory systems. The cerebellum also receives extensive inputs from the motion and gravity sensors in the vestibular labyrinth, but its role in the perception of head motion and orientation has received little attention. Drawing on the lesion-deficit approach to understanding brain function, we evaluated the contributions of the cerebellum to head motion perception by measuring perceptual thresholds in two subjects with congenital agenesis of the cerebellum. We used a set of passive motion paradigms that activated the semicircular canals or otolith organs in isolation or combination, and compared results of the agenesis patients with healthy control subjects. Perceptual thresholds for head motion were elevated in the agenesis subjects for all motion protocols, most prominently for paradigms that only activated otolith inputs. These results demonstrate that the cerebellum increases the sensitivity of the brain to the motion and orientation signals provided by the labyrinth during passive head movements., (Copyright © 2016 the American Physiological Society.)

Social networking sites (SNSs) have gained substantial popularity among youth in recent years. However, the relationship between the use of these Web-based platforms and mental health problems in children and adolescents is unclear. This study investigated the association between time spent on SNSs and unmet need for mental health support, poor self-rated mental health, and reports of psychological distress and suicidal ideation in a representative sample of middle and high school children in Ottawa, Canada. Data for this study were based on 753 students (55% female; Mage=14.1 years) in grades 7-12 derived from the 2013 Ontario Student Drug Use and Health Survey. Multinomial logistic regression was used to examine the associations between mental health variables and time spent using SNSs. Overall, 25.2% of students reported using SNSs for more than 2 hours every day, 54.3% reported using SNSs for 2 hours or less every day, and 20.5% reported infrequent or no use of SNSs. Students who reported unmet need for mental health support were more likely to report using SNSs for more than 2 hours every day than those with no identified unmet need for mental health support. Daily SNS use of more than 2 hours was also independently associated with poor self-rating of mental health and experiences of high levels of psychological distress and suicidal ideation. The findings suggest that students with poor mental health may be greater users of SNSs. These results indicate an opportunity to enhance the presence of health service providers on SNSs in order to provide support to youth.

Importance: Dizziness and imbalance are common clinical problems, and accurate diagnosis depends on determining whether damage is localized to the peripheral vestibular system. Vestibular testing guides this determination, but the accuracy of the different tests is not known., Objective: To determine how well each element of the vestibular test battery segregates patients with normal peripheral vestibular function from those with unilateral reductions in vestibular function., Design, Setting, and Participants: Retrospective analysis of vestibular test batteries in 8080 patients. Clinical medical records were reviewed for a subset of individuals with the reviewers blinded to the vestibular test data., Interventions: A group of machine-learning classifiers were trained using vestibular test data from persons who were "manually" labeled as having normal vestibular function or unilateral vestibular damage based on a review of their medical records. The optimal trained classifier was then used to categorize patients whose diagnoses were unknown, allowing us to determine the information content of each element of the vestibular test battery., Main Outcomes and Measures: The information provided by each element of the vestibular test battery to segregate individuals with normal vestibular function from those with unilateral vestibular damage., Results: The time constant calculated from the rotational test ranked first in information content, and measures that were related physiologically to the rotational time constant were 10 of the top 12 highest-ranked variables. The caloric canal paresis ranked eighth, and the other elements of the test battery provided minimal additional information. The sensitivity of the rotational time constant was 77.2%, and the sensitivity of the caloric canal paresis was 59.6%; the specificity of the rotational time constant was 89.0%, and the specificity of the caloric canal paresis was 64.9%. The diagnostic accuracy of the vestibular test battery increased from 72.4% to 93.4% when the data were analyzed with the optimal machine-learning classifier., Conclusions and Relevance: Rotational testing should be considered the primary test to diagnose unilateral peripheral vestibular damage in patients with dizziness or imbalance. Most physicians, however, continue to rely on caloric tests to guide their diagnoses. Our results support a significant shift in the approach used to determine diagnoses in patients with vestibular symptoms.

Although vestibular disorders are common and often disabling, they remain difficult to diagnose and treat. For these reasons, considerable interest has been focused on developing new ways to identify peripheral and central vestibular abnormalities and on new therapeutic options that could benefit the numerous patients who remain symptomatic despite optimal therapy. In this review, I focus on the potential utility of psychophysical vestibular testing and vestibular prosthetics. The former offers a new diagnostic approach that may prove to be superior to the current tests in some circumstances; the latter may be a way to provide the brain with information about head motion that restores some elements of the information normally provided by the vestibular labyrinth., (Copyright © 2015 the authors 0270-6474/15/355089-08$15.00/0.)

Loss of peripheral vestibular function results in debilitating postural, perceptual, and visual symptoms. A new approach to treating this clinical problem is to replace some aspects of peripheral vestibular function with a prosthesis that senses head motion and provides this information to the brain by stimulating the vestibular nerve. In this paper, I review studies done in animals over the past 15 years which lay the groundwork for transferring this approach to human patients with severe peripheral vestibular damage. The animal studies demonstrate that the visual and perceptual defects associated with peripheral vestibular damage can be improved with a vestibular implant, but the data on postural control remain less conclusive at this point in time., (© 2015 S. Karger AG, Basel.)

Vestibular migraine (VM), a common cause of vestibular symptoms within the general population, is a disabling and poorly understood form of dizziness. We sought to examine the underlying pathophysiology of VM with three studies, which involved the central synthesis of canal and otolith cues, and present preliminary results from each of these studies: (1) VM patients appear to have reduced motion perception thresholds when canal and otolith signals are modulated in a co-planar manner during roll tilt; (2) percepts of roll tilt appear to develop more slowly in VM patients than in control groups during a centrifugation paradigm that presents conflicting, orthogonal canal and otolith cues; and (3) eye movement responses appear to be different in VM patients when studied with a post-rotational tilt paradigm, which also presents a canal-otolith conflict, as the shift of the eye's rotational axis was larger in VM and the relationship between the axis shift and tilt suppression of the vestibulo-ocular reflex differed in VM patients relative to control groups. Based on these preliminary perceptual and eye movement results obtained with three different motion paradigms, we present a hypothesis that the integration of canal and otolith signals by the brain is abnormal in VM and that this abnormality could be cerebellar in origin. We provide potential mechanisms that could underlie these observations, and speculate that one of more of these mechanisms contributes to the vestibular symptoms and motion intolerance that are characteristic of the VM syndrome.

Background: Starting in 2008, the Central African Republic (CAR) experienced an unprecedented number of reported yellow fever (YF) cases. A risk assessment of YF virus (YFV) activity was conducted to estimate potential disease risk and vaccine needs., Methods: A multistage cluster sampling design was used to sample humans, non-human primates, and mosquitoes in distinct ecologic zones. Humans and non-human primates were tested for YFV-specific antibodies; mosquitoes were tested for YFV RNA., Results: Overall, 13.3% (125/938) of humans were found to have naturally-acquired YFV antibodies. Antibody levels were higher in zones in the southern and south central regions of CAR. All sampled non-human primates (n=56) were known YFV reservoirs; one tested positive for YFV antibodies. Several known YF vectors were identified including Aedes africanus, Ae. aegypti, Ae. luteocephalus, and Ae. simpsoni. Several more urban locations were found to have elevated Breateau and Container indices for Ae. aegypti., Conclusions: A country-wide assessment of YF risk found YFV to be endemic in CAR. The potential for future YF cases and outbreaks, however, varied by ecologic zone. Improved vaccination coverage through mass campaign and childhood immunization was recommended to mitigate the YF risk., (© The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We measured vestibular perceptual thresholds in patients with idiopathic bilateral vestibulopathy to assess the distribution of peripheral vestibular damage in this disorder. Thresholds were measured with standard psychometric techniques in 4 patients and compared with thresholds in normal subjects and patients with completely absent peripheral vestibular function. Motion paradigms included yaw rotation (testing the lateral canals), interaural translation (testing the utricles), superior-inferior translation (testing the saccules), and roll tilt (testing the vertical semicircular canals and the otolith organs). We found that perceptual thresholds were abnormally elevated in the patients with idiopathic bilateral vestibulopathy for yaw rotation at all frequencies and for interaural translation at only the lower frequencies. Thresholds were normal for the other 2 motion paradigms. The results demonstrate that the distribution of vestibular dysfunction in this disorder is not uniform but, rather, can affect lateral canal and utricular thresholds while relatively sparing vertical canal and saccular function., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Background: Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods., Methods and Findings: Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone. The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000-380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000-180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%-31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys., Conclusions: With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns.

Damage to one vestibular labyrinth or nerve causes a central tone imbalance, reflected by prominent spontaneous nystagmus. Central adaptive mechanisms eliminate the nystagmus over several days, and the mechanisms underlying this process have received extensive study. The characteristics of vestibular compensation when the tone imbalance is presented gradually or repeatedly have never been studied. We used high-frequency electrical stimulation of semicircular canal afferents to generate a vestibular tone imbalance and recorded the nystagmus produced when the stimulation was started abruptly or gradually and when it was repeatedly cycled on and off. In the acute-onset protocol, brisk nystagmus occurred when stimulation started, gradually resolved within 1 day, and reversed direction when the stimulation was stopped after 1 week. Repeated stimulation cycles resulted in progressively smaller nystagmus responses. In the slow-onset protocol, minimal nystagmus occurred while the stimulation ramped-up to its maximum rate over 12 h, but a reversal still occurred when the stimulation was stopped after 1 week, and repeated stimulation cycles did not affect this pattern. The absence of nystagmus during the 12 h ramp of stimulation demonstrates that central vestibular tone can rebalance relatively quickly, and the reduction in the stimulation-off nystagmus with repeated cycles of the acute-onset but not the slow-onset stimulation suggests that dual-state adaptation may have occurred with the former paradigm but not the latter.

Patients with vestibular dysfunction have visual, perceptual, and postural deficits. While there is considerable evidence that a semicircular canal prosthesis that senses angular head velocity and stimulates canal ampullary nerves can improve vision by augmenting the vestibulo-ocular reflex, no information is available regarding the potential utility of a canal prosthesis to improve perceptual deficits. In this study, we investigated the possibility that electrical stimulation of canal afferents could be used to modify percepts of head orientation. Two rhesus monkeys were trained to align a light bar parallel to gravity, and were tested in the presence and absence of electrical stimulation provided by an electrode implanted in the right posterior canal. While the monkeys aligned the light bar close to the true earth-vertical without stimulation, when the right posterior canal was stimulated their responses deviated toward their left ear, consistent with a misperception of head tilt toward the right. The deviation of the light bar from the earth-vertical exceeded the torsional deviation of the eyes, indicating that the perceptual changes were not simply visual in origin. Eye movements recorded during electrical stimulation in the dark were consistent with isolated activation of right posterior canal afferents, with no evidence of otolith stimulation. These results demonstrate that electrical stimulation of canal afferents affects the perception of head orientation, and therefore suggest that motion-modulated stimulation of canal afferents by a vestibular prosthesis could potentially improve vestibular percepts in patients lacking normal vestibular function.

Background: Serious, but rare adverse events following immunization (AEFI) have been reported with yellow fever (YF) 17D vaccine, including severe allergic reactions, YF vaccine-associated neurologic disease (YEL-AND) and YF vaccine-associated viscerotropic disease (YEL-AVD). The frequency with which YEL-AND and YEL-AVD occur in YF endemic countries is mostly unknown., Methods: From 2007 to 2010, eight African countries - Benin, Cameroon, Guinea, Liberia, Mali, Senegal, Sierra Leone, and Togo- implemented large-scale YF preventive vaccination campaigns. Each country established vaccine pharmacovigilance systems that included standard case definitions, procedures to collect and transport biological specimens, and National Expert Committees to review data and classify cases. Staff in all countries received training and laboratory capacity expanded., Results: In total, just over 38 million people were vaccinated against YF and 3116 AEFIs were reported of which 164 (5%) were classified as serious. Of these, 22 (13%) were classified as YF vaccine reactions, including 11 (50%) hypersensitivity reactions, six (27%) suspected YEL-AND, and five (23%) suspected YEL-AVD. The incidence per 100,000 vaccine doses administered was 8.2 for all reported AEFIs, 0.43 for any serious AEFI, 0.058 for YF vaccine related AEFIs, 0.029 for hypersensitivity reactions, 0.016 for YEL-AND, and 0.013 for YEL-AVD. Our findings were limited by operational challenges, including difficulties in obtaining recommended biological specimens leading to incomplete laboratory evaluation, unknown case ascertainment, and variable levels of staff training and experience., Conclusions: Despite limitations, active case-finding in the eight different countries did not find an incidence of YF vaccine associated AEFIs that was higher than previous reports. These data reinforce the safety profile of YF vaccine and support the continued use of attenuated YF vaccine during preventive mass vaccination campaigns in YF endemic areas., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose of Review: To summarize the recent progress in the development of vestibular implants. The review is timely because of the recent advances in the field and because MED-EL has recently announced that they are developing a vestibular implant for clinical applications., Recent Findings: The handicap experienced by patients suffering from bilateral vestibulopathy has a strong negative impact on physical and social functioning that appears to justify a surgical intervention. Two different surgical approaches to insert electrodes to stimulate ampullary neurons have been shown to be viable. The three-dimensional vestibulo-ocular reflex in rhesus monkeys produced with a three-dimensional vestibular implant showed gains that were relatively normal during acute stimulation. Rotation cues provided by an implant interact with otolith cues in a qualitatively normal manner. The brain appears to adapt plastically to the cues provided via artificial electrical stimulation., Summary: Research to date includes just a few human studies, but available data from both humans and animals support the technological and physiological feasibility of vestibular implants. Although vestibular implant users should not expect normal vestibular function - any more than cochlear implant users should expect normal hearing - data suggest that significant functional improvements are possible.

To assess the contributions of the vestibular system to whole-body motion discrimination in the dark, we measured direction recognition thresholds as a function of frequency for yaw rotation, superior-inferior translation ("z-translation"), interaural translation ("y-translation"), and roll tilt for 14 normal subjects and for 3 patients following total bilateral vestibular ablation. The patients had significantly higher average threshold measurements than normal (p < 0.01) for yaw rotation (depending upon frequency, 5.4× to 15.7× greater), z-translation (8.3× to 56.8× greater), y-translation (1.7× to 4.5× greater), and roll tilt (1.3× to 3.0× greater)--establishing the predominant contributions of the vestibular system for these motions in the dark.