Identifiability investigation of within-host models of acute virus infection.

Uncertainty in parameter estimates from fitting within-host models to empirical data limits the model's ability to uncover mechanisms of infection, disease progression, and to guide pharmaceutical interventions. Understanding the effect of model structure and data availability on model predictions is important for informing model development and experimental design. To address sources of uncertainty in parameter estimation, we use four mathematical models of influenza A infection with increased degrees of biological realism. We test the ability of each model to reveal its parameters in the presence of unlimited data by performing structural identifiability analyses. We then refine the results by predicting practical identifiability of parameters under daily influenza A virus titers alone or together with daily adaptive immune cell data. Using these approaches, we present insight into the sources of uncertainty in parameter estimation and provide guidelines for the types of model assumptions, optimal experimental design, and biological information needed for improved predictions. Author summary: Within-host models of virus infections fitted to data have improved our understanding of mechanisms of infection, disease progression, and allowed us to provide guidelines for pharmaceutical interventions. Given their predictive power, it is essential that we properly uncover and address uncertainty in model predictions and parameter estimation. Here, we focus on the effect of model structure and data availability on our ability to uncover unknown parameters. To address these questions, we use four mathematical models of influenza A infection with increased degrees of biological realism. We test the ability of each model to reveal its parameters in the presence of unlimited data by performing structural identifiability analysis. We then refine the results by predicting practical identifiability of parameters under daily influenza A virus titers alone or together with daily adaptive immune cell data. Using these approaches, we present insights into the sources of uncertainty in parameter estimations and provide guidelines for the types of model assumptions, optimal experimental design, and biological information needed for improved predictions.

The effect of model structure and data availability on Usutu virus dynamics at three biological scales.

Understanding the epidemiology of emerging pathogens, such as Usutu virus (USUV) infections, requires systems investigation at each scale involved in the host-virus transmission cycle, from individual bird infections, to bird-to-vector transmissions, and to USUV incidence in bird and vector populations. For new pathogens field data are sparse, and predictions can be aided by the use of laboratory-type inoculation and transmission experiments combined with dynamical mathematical modelling. In this study, we investigated the dynamics of two strains of USUV by constructing mathematical models for the within-host scale, bird-to-vector transmission scale and vector-borne epidemiological scale. We used individual within-host infectious virus data and per cent mosquito infection data to predict USUV incidence in birds and mosquitoes. We addressed the dependence of predictions on model structure, data uncertainty and experimental design. We found that uncertainty in predictions at one scale change predicted results at another scale. We proposed in silico experiments that showed that sampling every 12 hours ensures practical identifiability of the within-host scale model. At the same time, we showed that practical identifiability of the transmission scale functions can only be improved under unrealistically high sampling regimes. Instead, we proposed optimal experimental designs and suggested the types of experiments that can ensure identifiability at the transmission scale and, hence, induce robustness in predictions at the epidemiological scale.

Late-onset epilepsy with cognitive symptoms: Comparison of cognitive and imaging profiles with probable Alzheimer's disease.

OBJECTIVE: We aimed to (i) compare the clinical, neuropsychological, and neuroimaging characteristics of unprovoked late-onset epilepsy (LOE) patients with cognitive symptoms against probable Alzheimer's disease (AD) patients; (ii) clarify how neurodegeneration and other processes could be implicated in the cognitive symptoms of unprovoked LOE patients; and (iii) characterize the longitudinal trajectory of unprovoked LOE patients with cognitive symptoms. METHODS: Twenty-six unprovoked LOE patients with cognitive symptoms and 26 probable AD were retrospectively recruited from epilepsy and memory clinics at a single tertiary referral center. The patients underwent comprehensive clinical, neuropsychological, and 18Fluorodeoxyglucose PET-CT assessments. All LOE patients had clinical follow-up and a subset of 17 patients had repeat neuropsychological assessments. RESULTS: At baseline, 18% of LOE patients with cognitive symptoms had dementia-range cognitive impairment and one received a diagnosis of probable AD. Compared with the probable AD group, the LOE group did not perform significantly better in global measures of cognition (total ACE-III), neuropsychological tests for fluency, working memory, language, attention, or executive function, but performed better in naming, memory, and visuospatial ability. The commonest patterns of cognitive impairment in the LOE group were frontal and left temporal, whereas all AD patients exhibited parietotemporal patterns. The AD group had more 18Fluorodeoxyglucose PET-CT hypometabolism in the parietal and occipital, but not the temporal and frontal lobes. During the 3.0 ± 3.2 years follow-up, improved seizure frequency in the LOE group covaried with improved total ACE-III score, there was no further conversion to probable AD and no group-level cognitive decline. CONCLUSION: Unprovoked LOE patients with cognitive symptoms had varying severities of cognitive impairment, and different patterns of cognitive and imaging abnormalities compared with AD patients. They were rarely diagnosed with probable AD at presentation or follow-up. Cognitive outcome in LOE may be related to seizure control. Cerebral small vessel disease may play a role in LOE-associated cognitive impairment.

Déjà vécu with recollective confabulation: an unusual presentation of Alzheimer's disease.

A man in his 80s presented with gradual onset of a persistent and delusion-like perception that novel encounters are repetitions of previous experiences. Within 2 years of symptom onset, he had impaired verbal memory and executive dysfunction on neuropsychological assessment. Cerebrospinal fluid core Alzheimer's disease (AD) biomarkers analysis supported probable AD. Generalised and left temporal atrophy was seen on MRI of the brain. Neurological fludeoxyglucose-positron emission tomography (PET)/CT showed left temporal and bilateral frontal lobe hypometabolism. His presenting symptom is known as déjà vécu with recollective confabulation, a rare phenomenon associated with AD and other neurodegenerative disorders. While several potential mechanisms have been previously proposed, the fludeoxyglucose-PET/CT hypometabolism in the temporal and frontal lobes in this case suggests dual deficits in recognition memory and metacognition may be culprit mechanisms. Although uncommon, déjà vécu with recollective confabulation is a fascinating phenomenon that can provide a unique insight into memory and delusional processes in dementia.

Modeling within-host and aerosol dynamics of SARS-CoV-2: The relationship with infectiousness.

The relationship between transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the amount of virus present in the proximity of a susceptible host is not understood. Here, we developed a within-host and aerosol mathematical model and used it to determine the relationship between viral kinetics in the upper respiratory track, viral kinetics in the aerosols, and new transmissions in golden hamsters challenged with SARS-CoV-2. We determined that infectious virus shedding early in infection correlates with transmission events, shedding of infectious virus diminishes late in the infection, and high viral RNA levels late in the infection are a poor indicator of transmission. We further showed that viral infectiousness increases in a density dependent manner with viral RNA and that their relative ratio is time-dependent. Such information is useful for designing interventions.

Subjective Cognitive Dysfunction in Patients with Dizziness and Vertigo.

INTRODUCTION: Patients with vestibular disorders sometimes report cognitive difficulties, but there is no consensus about the type or degree of cognitive complaint. We therefore investigated subjective cognitive dysfunction in a well-defined sample of neuro-otology patients and used demographic factors and scores from a measure of depression, anxiety, and stress to control for potential confounding factors. METHODS: We asked 126 neuro-otology clinic outpatients whether they experienced difficulties with thinking, memory, or concentration as a result of dizziness or vertigo. They and 42 nonvertiginous control subjects also completed the Neuropsychological Vertigo Inventory (NVI, which measures cognitive, emotional, vision, and motor complaints), the Everyday Memory Questionnaire (EMQ), and Depression, Anxiety, and Stress Scales (DASS). RESULTS: In the initial interview questions, 60% of patients reported experiencing cognitive difficulties. Cognitive questionnaire scores were positively correlated with the overall DASS score and to a lesser extent with age and gender. Therefore, we compared patients and controls on the NVI and EMQ, using these mood and demographic variables as covariates. Linear regression analyses revealed that patients scored significantly worse on the total NVI, NVI cognitive composite, and 3 individual NVI cognition subscales (Attention, Space Perception, and Time Perception), but not the EMQ. Patients also scored significantly worse on the NVI Emotion and Motor subscales. CONCLUSIONS: Patients with dizziness and vertigo reported high levels of cognitive dysfunction, affecting attention, perceptions of space and time. Although perceptions of cognitive dysfunction were correlated with emotional distress, they were significantly elevated in patients over and above the impact of depression, anxiety, or stress.

Modeling the dynamics of Usutu virus infection in birds.

Usutu virus is an emerging zoonotic flavivirus causing high avian mortality rates and occasional severe neurological disorders in humans. Several virus strains are co-circulating and the differences in their characteristics and avian pathogenesis levels are still unknown. In this study, we use within-host mathematical models to characterize the mechanisms responsible for virus expansion and clearance in juvenile chickens challenged with four Usutu virus strains. We find heterogeneity between the virus strains, with the time between cell infection and viral production varying between 16 h and 23 h, the infected cell lifespan varying between 48 min and 9.5 h, and the basic reproductive number R0 varying between 12.05 and 19.49. The strains with high basic reproductive number have short infected cell lifespan, indicative of immune responses. The virus strains with low basic reproductive number have lower viral peaks and longer lasting viremia, due to lower infection rates and high infected cell lifespan. We discuss how the host and virus heterogeneities may differently impact the public health threat presented by these virus strains.

Pathogenesis and shedding of Usutu virus in juvenile chickens.

Usutu virus (USUV; family: Flaviviridae, genus: Flavivirus), is an emerging zoonotic arbovirus that causes severe neuroinvasive disease in humans and has been implicated in the loss of breeding bird populations in Europe. USUV is maintained in an enzootic cycle between ornithophilic mosquitos and wild birds. As a member of the Japanese encephalitis serocomplex, USUV is closely related to West Nile virus (WNV) and St. Louis encephalitis virus (SLEV), both neuroinvasive arboviruses endemic in wild bird populations in the United States. An avian model for USUV is essential to understanding zoonotic transmission. Here we describe the first avian models of USUV infection with the development of viremia. Juvenile commercial ISA Brown chickens were susceptible to infection by multiple USUV strains with evidence of cardiac lesions. Juvenile chickens from two chicken lines selected for high (HAS) or low (LAS) antibody production against sheep red blood cells showed markedly different responses to USUV infection. Morbidity and mortality were observed in the LAS chickens, but not HAS chickens. LAS chickens had significantly higher viral titers in blood and other tissues, as well as oral secretions, and significantly lower development of neutralizing antibody responses compared to HAS chickens. Mathematical modelling of virus-host interactions showed that the viral clearance rate is a stronger mitigating factor for USUV viremia than neutralizing antibody response in this avian model. These chicken models provide a tool for further understanding USUV pathogenesis in birds and evaluating transmission dynamics between avian hosts and mosquito vectors.

Rheumatoid leptomeningitis presenting with an acute neuropsychiatric disorder.

Leptomeningitis is a rare central nervous system manifestation of rheumatoid arthritis, generally in patients with established chronic rheumatoid disease. We report a 41-year-old man without previous rheumatoid arthritis or psychiatric disorder who presented with an acute neuropsychiatric disturbance and polyarthralgia. His MR scan of brain showed asymmetric bifrontal leptomeningitis, confirmed on (18F)-fluoro-D-glucose-positron emission tomography. Other investigations showed highly positive serum and cerebrospinal fluid anti-cyclic citrullinated peptide. A leptomeningeal biopsy showed necrotising leptomeningeal inflammation with ill-defined granulomas and lymphoplasmacytic infiltrate without organisms. Prolonged high-dose corticosteroids and then rituximab resulted in recovery. Chronic leptomeningitis can present with an acute neuropsychiatric disorder. We highlight that early rheumatoid disease can, rarely, cause a chronic leptomeningitis, reversible with immunotherapy.

Déjà vecu for news events but not personal events: A dissociation between autobiographical and non-autobiographical episodic memory processing.

In déjà vu, the feeling that what we are currently experiencing we have experienced before is fleeting and is not accepted as true. In contrast, in déjà vecu or "recollective confabulation", the sense of déjà vu is persistent and convincing, and patients genuinely believe that they have lived through the current moment at some previous time. In previous reports of cases of déjà vecu, both personal events and non-personal, world events gave rise to this experience. In this paper we describe a patient whose déjà vecu experiences are entirely restricted to non-personal events, suggesting that autobiographical and non-autobiographical episodic memory processing can dissociate. We suggest that this dissociation is secondary to differences in the degree to which personal and emotional associations are formed for these two different types of event, and offer a two-factor theory of déjà vecu.

Emergence and progression of 'non-semantic' deficits in semantic dementia.

Although semantic dementia (SD) is defined as a selective disruption of conceptual knowledge, a number of group studies have now demonstrated that SD patients also show impaired performance on tasks not usually considered to have a high semantic load (e.g., reading words aloud and lexical or object decision). The aim of the current study was to document the relative deterioration, over time, of a number of semantic and so-called 'non-semantic' tasks in LF, a single case of SD for whom - by virtue of his work as a published cartoonist - we also have extensive data regarding his pre-morbid linguistic and drawing skills. In five testing rounds over a period of five years we administered semantic tests of object naming and object definition (on both of which LF was progressively impaired, as expected for a diagnosis of SD), plus verbal and non-verbal 'non-semantic' tasks of reading aloud, spelling, object and lexical decision, and delayed copy drawing. Initially, his only striking 'non-semantic' deficit was in the domain of spelling - a pronounced surface dysgraphia in an individual with demonstrably superior pre-morbid spelling skill. Over time, and in line with his declining semantic system, LF's performance gradually deteriorated on all of the 'non-semantic' tasks. The most vulnerable items on most tasks were those with low frequency and an atypical form. This report adds to the growing body of evidence that a number of cognitive processes not usually considered to be 'semantic' in their demands rely on the integrity of semantic knowledge for successful execution. Furthermore, it provides the first indication that these non-semantic deficits might emerge in an order predictable from the typicality structure of the relevant domain.

Developing hypnotic analogues of clinical delusions: mirrored-self misidentification.

INTRODUCTION: Despite current research interest in delusional beliefs, there are no viable models for studying delusions in the laboratory. However, hypnosis offers a technique for creating transient delusions that are resistant to challenge. The aim of this study was to develop an hypnotic analogue of one important delusion, mirrored-self misidentification. METHODS: Twelve high hypnotisable participants received an hypnotic suggestion to see either a stranger in the mirror, a mirror as a window, or a mirror as a window with a view to a stranger. Participants' deluded beliefs were challenged, and following hypnosis, Sheehan and McConkey's (1982) Experiential Analysis Technique was used to explore participants' phenomenological experience of the delusion. RESULTS: The majority of participants did not recognise their reflection in the mirror, described the person in the mirror as having different physical characteristics to themselves, and maintained their delusion when challenged. CONCLUSIONS: The hypnotic suggestion created a credible, compelling delusion with features strikingly similar to clinical cases of mirrored-self misidentification. Our findings suggest that Factor 2 within Langdon and Coltheart's (2000) two-factor framework may involve a lowering of the criteria used to accept or reject delusional hypotheses.

The recognition of emotional expression in prosopagnosia: decoding whole and part faces.

Prosopagnosia is currently viewed within the constraints of two competing theories of face recognition, one highlighting the analysis of features, the other focusing on configural processing of the whole face. This study investigated the role of feature analysis versus whole face configural processing in the recognition of facial expression. A prosopagnosic patient, SC made expression decisions from whole and incomplete (eyes-only and mouth-only) faces where features had been obscured. SC was impaired at recognizing some (e.g., anger, sadness, and fear), but not all (e.g., happiness) emotional expressions from the whole face. Analyses of his performance on incomplete faces indicated that his recognition of some expressions actually improved relative to his performance on the whole face condition. We argue that in SC interference from damaged configural processes seem to override an intact ability to utilize part-based or local feature cues.

Anarchic hand syndrome: bimanual coordination and sensitivity to irrelevant information in unimanual reaches.

Anarchic hand syndrome is characterised by unintended but purposeful and autonomous movements of the upper limb and intermanual conflict. Based on predictions of internal models of movement generation, we examined the role of visual cues in unimanual and bimanual movements in a patient with anarchic hand syndrome and in a matched control. In Experiment 1, participants made unimanual movements in a sequential button-pressing task. The cue for the next target in a sequence appeared either prior to (exogenous) or after (endogenous) the initiation of movement. For the patient, performance of the anarchic left hand was selectively impaired in the endogenous condition. In Experiment 2, participants made unimanual movements on a digitising tablet to a target, which appeared either alone or with a distractor. While the presence of a distractor was associated with increased Initiation time in general, the patient's anarchic left hand was particularly vulnerable to disruption by the distractor. The findings of Experiments 1 and 2 indicate excessive reliance on salient environmental stimuli for movement production in anarchic hand syndrome. We conclude that in AHS goal-directed actions of the affected limb are particularly vulnerable to disruption by non-relevant information. Finally, in Experiment 3, participants performed unimanual and mirror-image bimanual movements on a digitising tablet to targets in the left or right hemispace. Coupling of the parameters of the two hands was evident such that, compared with a unimanual baseline, Initiation time of the intact right hand deteriorated while it improved for the anarchic left hand.

The role of affect and reasoning in a patient with a delusion of misidentification.

INTRODUCTION: This study investigated a patient with a delusion of misidentification (DM) resembling a Capgras delusion. Instead of the typical Capgras delusion--the false belief that someone has been replaced by an almost identical impostor--patient MF misidentified his wife as his former business partner. METHOD: Detailed investigation of MF's face processing, affective response and affect perception, and ability to evaluate, and reject, implausible ideas was undertaken. RESULTS: MF's visual processing of identity, gender, and age of familiar and unknown faces was intact but he was unable to identify the facial expressions of anger, disgust, and fear, or to match faces across expressions. MF also showed a reduced affective responsiveness to his environment, and impaired reasoning ability. CONCLUSIONS: We propose that MF's delusion of misidentification resulted from a combination of affective deficits, including impairment of both affective response and affect perception, in addition to an inability to evaluate, and reject, implausible ideas. These deficits, in combination with specific life events at the time of onset of the delusion, may have contributed to the form and content of the delusion. In addition, the results raise the possibility that the processing of face identity and facial expression are not as independent as previously proposed in models of face processing.