Resting-state EEG reveals four subphenotypes of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating disease characterized primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. Amyotrophic lateral sclerosis is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in amyotrophic lateral sclerosis. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (comodulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localized brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that amyotrophic lateral sclerosis patients (n = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterized by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (ß-band neural activity and γl-band synchrony) and frontoparietal (γl-band comodulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after reassessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of amyotrophic lateral sclerosis subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in amyotrophic lateral sclerosis can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption.

More than words: Neurophysiological correlates of semantic dissimilarity depend on comprehension of the speech narrative.

Speech comprehension relies on the ability to understand words within a coherent context. Recent studies have attempted to obtain electrophysiological indices of this process by modelling how brain activity is affected by a word's semantic dissimilarity to preceding words. Although the resulting indices appear robust and are strongly modulated by attention, it remains possible that, rather than capturing the contextual understanding of words, they may actually reflect word-to-word changes in semantic content without the need for a narrative-level understanding on the part of the listener. To test this, we recorded electroencephalography from subjects who listened to speech presented in either its original, narrative form, or after scrambling the word order by varying amounts. This manipulation affected the ability of subjects to comprehend the speech narrative but not the ability to recognise individual words. Neural indices of semantic understanding and low-level acoustic processing were derived for each scrambling condition using the temporal response function. Signatures of semantic processing were observed when speech was unscrambled or minimally scrambled and subjects understood the speech. The same markers were absent for higher scrambling levels as speech comprehension dropped. In contrast, word recognition remained high and neural measures related to envelope tracking did not vary significantly across scrambling conditions. This supports the previous claim that electrophysiological indices based on the semantic dissimilarity of words to their context reflect a listener's understanding of those words relative to that context. It also highlights the relative insensitivity of neural measures of low-level speech processing to speech comprehension.

Utility of a Telephone Triage Hotline in Response to the COVID-19 Pandemic: Longitudinal Observational Study.

BACKGROUND: During the initial months of the COVID-19 pandemic, rapidly rising disease prevalence in the United States created a demand for patient-facing information exchanges that addressed questions and concerns about the disease. One approach to managing increased patient volumes during a pandemic involves the implementation of telephone-based triage systems. During a pandemic, telephone triage hotlines can be employed in innovative ways to conserve medical resources and offer useful population-level data about disease symptomatology and risk factor profiles. OBJECTIVE: The aim of this study is to describe and evaluate the COVID-19 telephone triage hotline used by a large academic medical center in the midwestern United States. METHODS: Michigan Medicine established a telephone hotline to triage inbound patient calls related to COVID-19. For calls received between March 24, 2020, and May 5, 2020, we described total call volume, data reported by callers including COVID-19 risk factors and symptomatology, and distribution of callers to triage algorithm endpoints. We also described symptomatology reported by callers who were directed to the institutional patient portal (online medical visit questionnaire). RESULTS: A total of 3929 calls (average 91 calls per day) were received by the call center during the study period. The maximum total number of daily calls peaked at 211 on March 24, 2020. Call volumes were the highest from 6 AM to 11 AM and during evening hours. Callers were most often directed to the online patient portal (1654/3929, 42%), nursing hotlines (1338/3929, 34%), or employee health services (709/3929, 18%). Cough (126/370 of callers, 34%), shortness of breath (101/370, 27%), upper respiratory infection (28/111, 25%), and fever (89/370, 24%) were the most commonly reported symptoms. Immunocompromised state (23/370, 6%) and age >65 years (18/370, 5%) were the most commonly reported risk factors. CONCLUSIONS: The triage algorithm successfully diverted low-risk patients to suitable algorithm endpoints, while directing high-risk patients onward for immediate assessment. Data collected from hotline calls also enhanced knowledge of symptoms and risk factors that typified community members, demonstrating that pandemic hotlines can aid in the clinical characterization of novel diseases.

Semantic Context Enhances the Early Auditory Encoding of Natural Speech.

Speech perception involves the integration of sensory input with expectations based on the context of that speech. Much debate surrounds the issue of whether or not prior knowledge feeds back to affect early auditory encoding in the lower levels of the speech processing hierarchy, or whether perception can be best explained as a purely feedforward process. Although there has been compelling evidence on both sides of this debate, experiments involving naturalistic speech stimuli to address these questions have been lacking. Here, we use a recently introduced method for quantifying the semantic context of speech and relate it to a commonly used method for indexing low-level auditory encoding of speech. The relationship between these measures is taken to be an indication of how semantic context leading up to a word influences how its low-level acoustic and phonetic features are processed. We record EEG from human participants (both male and female) listening to continuous natural speech and find that the early cortical tracking of a word's speech envelope is enhanced by its semantic similarity to its sentential context. Using a forward modeling approach, we find that prediction accuracy of the EEG signal also shows the same effect. Furthermore, this effect shows distinct temporal patterns of correlation depending on the type of speech input representation (acoustic or phonological) used for the model, implicating a top-down propagation of information through the processing hierarchy. These results suggest a mechanism that links top-down prior information with the early cortical entrainment of words in natural, continuous speech.SIGNIFICANCE STATEMENT During natural speech comprehension, we use semantic context when processing information about new incoming words. However, precisely how the neural processing of bottom-up sensory information is affected by top-down context-based predictions remains controversial. We address this discussion using a novel approach that indexes a word's similarity to context and how well a word's acoustic and phonetic features are processed by the brain at the time of its utterance. We relate these two measures and show that lower-level auditory tracking of speech improves for words that are more related to their preceding context. These results suggest a mechanism that links top-down prior information with bottom-up sensory processing in the context of natural, narrative speech listening.

Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a terminal progressive adult-onset neurodegeneration of the motor system. Although originally considered a pure motor degeneration, there is increasing evidence of disease heterogeneity with varying degrees of extra-motor involvement. How the combined motor and nonmotor degeneration occurs in the context of broader disruption in neural communication across brain networks has not been well characterized. Here, we have performed high-density crossectional and longitudinal resting-state electroencephalography (EEG) recordings on 100 ALS patients and 34 matched controls, and have identified characteristic patterns of altered EEG connectivity that have persisted in longitudinal analyses. These include strongly increased EEG coherence between parietal-frontal scalp regions (in γ-band) and between bilateral regions over motor areas (in θ-band). Correlation with structural MRI from the same patients shows that disease-specific structural degeneration in motor areas and corticospinal tracts parallels a decrease in neural activity over scalp motor areas, while the EEG over the scalp regions associated with less extensively involved extra-motor regions on MRI exhibit significantly increased neural communication. Our findings demonstrate that EEG-based connectivity mapping can provide novel insights into progressive network decline in ALS. These data pave the way for development of validated cost-effective spectral EEG-based biomarkers that parallel changes in structural imaging.

Patterned functional network disruption in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor function, with additional evidence of extensive nonmotor involvement. Despite increasing recognition of the disease as a multisystem network disorder characterised by impaired connectivity, the precise neuroelectric characteristics of impaired cortical communication remain to be fully elucidated. Here, we characterise changes in functional connectivity using beamformer source analysis on resting-state electroencephalography recordings from 74 ALS patients and 47 age-matched healthy controls. Spatiospectral characteristics of network changes in the ALS patient group were quantified by spectral power, amplitude envelope correlation (co-modulation) and imaginary coherence (synchrony). We show patterns of decreased spectral power in the occipital and temporal (δ- to ß-band), lateral/orbitofrontal (δ- to θ-band) and sensorimotor (ß-band) regions of the brain in patients with ALS. Furthermore, we show increased co-modulation of neural oscillations in the central and posterior (δ-, θ- and γl -band) and frontal (δ- and γl -band) regions, as well as decreased synchrony in the temporal and frontal (δ- to ß-band) and sensorimotor (ß-band) regions. Factorisation of these complex connectivity patterns reveals a distinct disruption of both motor and nonmotor networks. The observed changes in connectivity correlated with structural MRI changes, functional motor scores and cognitive scores. Characteristic patterned changes of cortical function in ALS signify widespread disease-associated network disruption, pointing to extensive dysfunction of both motor and cognitive networks. These statistically robust findings, that correlate with clinical scores, provide a strong rationale for further development as biomarkers of network disruption for future clinical trials.

A population pharmacokinetic modeling approach shows that serum penicillin G concentrations are below inhibitory concentrations by two weeks after benzathine penicillin G injection in the majority of young adults.

Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

Trends in meningococcal disease in the United States military, 1971-2010.

Meningococci have historically caused extensive illness among members of the United States military. Three successive meningococcal vaccine types were used from 1971 through 2010; overall disease incidence dropped by >90% during this period. During 2006-2010, disease incidence of 0.38 (cases per 100,000 person-years) among members of the US military was not significantly different from the incidence of 0.26 among the age-matched US general population. Of the 26 cases in the US military, 5 were fatal, 15 were vaccine failures (e.g., illness in a person who had been vaccinated), and 9 were caused by Neisseria meningitidis serogroup Y. Incidences among 17- to 19-year-old basic trainees and among US Marines were significantly higher than among comparison military populations (p<0.05). No apparent change in epidemiology of meningococcal disease was observed after replacement of quadrivalent polysaccharide vaccine with conjugate vaccine in 2007. The data demonstrate that vaccination with meningococcal vaccine is effective.

Fabrication and activity of silicate nanoparticles and nanosilicate-entrapped enzymes using polyethyleneimine as a biomimetic polymer.

In nature, some peptides induce precipitation of silicic acid into silica nanoparticles such as is found in marine algae called diatoms. However, polybasic polymers can act as peptide mimics; one such polymer, polyethyleneimine (PEI), has the advantage that it is stable at room temperature and is inexpensive, in comparison with synthetic peptides. We describe the fabrication and characterization of biosilicate nanoparticles formed by mimicking the peptides using PEI. Brownian motion nanoparticle tracking analysis and field emission gun scanning electron microscopy have been used for the first time to characterize nanoparticles made with tetramethyl orthosilicate (TMOS) and PEI to investigate the fundamental factors that affect particle properties. These factors include the effect of phosphate concentration, PEI molecular weight, TMOS concentration, and species of alkoxy-silane used. The properties of the particles are compared with other particles made with polymers that induce silication. Our results show that using PEI gives differences in particle size compared with previous work using other polymers that induce silication. The entrapment of enzymes during the silication process, rationale for using nonphosphate and phosphate buffers during enzyme entrapment, and the analysis of enzyme activity are also presented. Because enzymes can be entrapped during fabrication, it means that there are many future possibilities for the use of silicate nanoparticles containing enzymes, such as biosensors and biocatalytic reactors.

U.S. military fatalities due to Neisseria meningitidis: case reports and historical perspective.

Meningococcal disease has historically been associated with military populations, particularly during periods of mobilization. Although the U.S. military has now been engaged in conflicts for nearly a decade, the incidence of meningococcal disease in the U.S. population as a whole has reached historic lows. Despite vaccination of all service members in basic military training, the risk of meningococcal disease appears to be equal to or greater than that of the civilian population. These 3 case reports of recent fatalities in the U.S. military and their historic contexts illustrate the circumstances under which meningococcus can strike and highlight the need for continued vigilance in military populations.

Dissociable electrophysiological measures of natural language processing reveal differences in speech comprehension strategy in healthy ageing.

Healthy ageing leads to changes in the brain that impact upon sensory and cognitive processing. It is not fully clear how these changes affect the processing of everyday spoken language. Prediction is thought to play an important role in language comprehension, where information about upcoming words is pre-activated across multiple representational levels. However, evidence from electrophysiology suggests differences in how older and younger adults use context-based predictions, particularly at the level of semantic representation. We investigate these differences during natural speech comprehension by presenting older and younger subjects with continuous, narrative speech while recording their electroencephalogram. We use time-lagged linear regression to test how distinct computational measures of (1) semantic dissimilarity and (2) lexical surprisal are processed in the brains of both groups. Our results reveal dissociable neural correlates of these two measures that suggest differences in how younger and older adults successfully comprehend speech. Specifically, our results suggest that, while younger and older subjects both employ context-based lexical predictions, older subjects are significantly less likely to pre-activate the semantic features relating to upcoming words. Furthermore, across our group of older adults, we show that the weaker the neural signature of this semantic pre-activation mechanism, the lower a subject's semantic verbal fluency score. We interpret these findings as prediction playing a generally reduced role at a semantic level in the brains of older listeners during speech comprehension and that these changes may be part of an overall strategy to successfully comprehend speech with reduced cognitive resources.

Applying to be Doctors of Tomorrow: A Qualitative Study Exploring Motivations Towards Applying to a Medical Pipeline Program.

PURPOSE: To identify the motivations of adolescent students applying into medical pipeline programs that are focused on populations underrepresented in medicine. METHODS: The Doctors of Tomorrow (DoT) program is a medical pipeline program between the University of Michigan Medical School and Cass Technical High School in Detroit, Michigan, USA. As a component of the application process, ninth-grade students complete multiple free response essays that allow students to articulate their reasons for applying and their goals for participation in the program. Between 2013 and 2019, 323 ninth-grade students applied to DoT and 216 were accepted. The authors qualitatively analyzed all applications using theoretical coding methods to identify common themes discussed by students regarding their motivations for applying. The authors used Dedoose 8.3.17 (Los Angeles, CA) for qualitative analysis. RESULTS: Four main themes emerged after coding and thematic analysis: (1) Career Aspiration, (2) Exposure to the Medical Field, (3) Breadth of Mentorship, and (4) Longitudinal Professional Development. 'Health Disparities in Minority Communities,' a code used when students commented on issues of race, social determinants of health, and health disparities as motivators, was not identified as frequently as the other codes, despite it being a main topic within the pipeline program. CONCLUSIONS: Applicants to medical school pipeline programs articulate similar intrinsic motivations that can be used to inform what drives students to apply. Pipeline programs should consider these intrinsic motivations, while also creating structured activities from which students can learn and gain tangible benefits when designing curricula. While ninth-grade students acknowledge health disparities in minority communities, their current level of personal experience may not lead them to identify these disparities as significant motivators, and pipeline leaders should be aware of this when designing lesson plans concerning these topics.

The Reporting of Race and Ethnicity in Surgery Literature.

Importance: The reporting of race provides transparency to the representativeness of data and helps inform health care disparities. The International Committee of Medical Journal Editors (ICMJE) developed recommendations to promote quality reporting of race; however, the frequency of reporting continues to be low among most medical journals. Objective: To assess the frequency as well as quality of race reporting among publications from high-ranking broad-focused surgical research journals. Design, Setting, and Participants: A literature review and bibliometric analysis was performed examining all human-based primary research articles published in 2019 from 7 surgical journals: JAMA Surgery, Journal of the American College of Surgeons, Annals of Surgery, Surgery, American Journal of Surgery, Journal of Surgical Research, and Journal of Surgical Education. The 5 journals that stated they follow the ICMJE recommendations were analyzed against the 2 journals that did not explicitly claim adherence. Main Outcomes and Measures: Measured study outcomes included race reporting frequency and use of the ICMJE recommendations for quality reporting of race. Results: A total of 2485 publications were included in the study. The mean (SD) frequency of reporting of race and ethnicity in publications of ICMJE vs non-ICMJE journals was 32.8% (8.4) and 32.0% (20.9), respectively (P = .72). Adherence to ICMJE recommendations for reporting race was more frequent in ICMJE journals than non-ICMJE journals (mean [SD] of 73.1% [17.8] vs 37.0% [10.2]; P < .001). Conclusions and Relevance: The frequency of race and ethnicity reporting among surgical journals is low. A journal's statement of adherence to ICMJE recommendations did not affect the frequency of race and ethnicity reporting; however, there was an increase in the use of ICMJE quality metrics. These findings suggest the need for increased and more standardized reporting of racial and ethnic demographic data among surgical journals.

Effects of Moringa Extract on Aminoglycoside-Induced Hair Cell Death and Organ of Corti Damage.

HYPOTHESIS: Moringa extract, a naturally occurring anti-oxidant, protects against aminoglycoside-induced hair cell death and hearing loss within the organ of Corti. BACKGROUND: Reactive oxygen species (ROS) arise primarily in the mitochondria and have been implicated in aminoglycoside-induced ototoxicity. Mitochondrial dysfunction results in loss of membrane potential, release of caspases, and cell apoptosis. Moringa extract has not previously been examined as a protective agent for aminoglycoside-induced ototoxicity. METHODS: Putative otoprotective effects of moringa extract were investigated in an organotypic model using murine organ of Corti explants subjected to gentamicin-induced ototoxicity. Assays evaluated hair cell loss, cytochrome oxidase expression, mitochondrial membrane potential integrity, and caspase activity. RESULTS: In vitro application of moringa conferred significant protection from gentamicin-induced hair cell loss at dosages from 25 to 300 µg/mL, with dosages above 100 µg/mL conferring near complete protection. Assays demonstrated moringa extract suppression of ROS, preservation of cytochrome oxidase activity, and reduction in caspase production. CONCLUSION: Moringa extract demonstrated potent antioxidant properties with significant protection against gentamicin ototoxicity in cochlear explants.

Cognitive network hyperactivation and motor cortex decline correlate with ALS prognosis.

We aimed to quantitatively characterize progressive brain network disruption in Amyotrophic Lateral Sclerosis (ALS) during cognition using the mismatch negativity (MMN), an electrophysiological index of attention switching. We measured the MMN using 128-channel EEG longitudinally (2-5 timepoints) in 60 ALS patients and cross-sectionally in 62 healthy controls. Using dipole fitting and linearly constrained minimum variance beamforming we investigated cortical source activity changes over time. In ALS, the inferior frontal gyri (IFG) show significantly lower baseline activity compared to controls. The right IFG and both superior temporal gyri (STG) become progressively hyperactive longitudinally. By contrast, the left motor and dorsolateral prefrontal cortices are initially hyperactive, declining progressively. Baseline motor hyperactivity correlates with cognitive disinhibition, and lower baseline IFG activities correlate with motor decline rate, while left dorsolateral prefrontal activity predicted cognitive and behavioural impairment. Shorter survival correlates with reduced baseline IFG and STG activity and later STG hyperactivation. Source-resolved EEG facilitates quantitative characterization of symptom-associated and symptom-preceding motor and cognitive-behavioral cortical network decline in ALS.

Broad spectrum respiratory pathogen analysis of throat swabs from military recruits reveals interference between rhinoviruses and adenoviruses.

Military recruits experience a high incidence of febrile respiratory illness (FRI), leading to significant morbidity and lost training time. Adenoviruses, group A Streptococcus pyogenes, and influenza virus are implicated in over half of the FRI cases reported at recruit training center clinics, while the etiology of the remaining cases is unclear. In this study, we explore the carriage rates and disease associations of adenovirus, enterovirus, rhinovirus, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis in military recruits using high-density resequencing microarrays. The results showed that rhinoviruses, adenoviruses, S. pneumoniae, H. influenzae, and N. meningitidis were widely distributed in recruits. Of these five agents, only adenovirus showed significant correlation with illness. Among the samples tested, only pathogens associated with FRI, such as adenovirus 4 and enterovirus 68, revealed strong temporal and spatial clustering of specific strains, indicating that they are transmitted primarily within sites. The results showed a strong negative association between adenoviral FRI and the presence of rhinoviruses in recruits, suggesting some form of viral interference.

Head and Neck Reconstruction in the Vessel Depleted Neck.

Microvascular free tissue transfer has revolutionized reconstruction and subsequently functional outcomes in the head and neck, but requires suitable recipient vessels for successful results. Recipient vessels can be significantly compromised by prior surgery, radiation therapy, or existing and/or underlying vascular disease in the neck. When further microvascular reconstruction is required in the vessel-depleted neck, identification of appropriate vessels for anastomosis can be difficult and can present complex decisions for the surgeon as well as the patient. In this article, we review the available literature on the vessel depleted neck and the possible vessel options. We present critical strategies for preoperative treatment planning and vessel selection in these patients. We also discuss the benefits and limitations of arterial and venous options while commenting on our unique institution's experiences. The external carotid branches as well as the available subclavian artery branches are presented in detail. The venous anatomy is also described, with particular focus on the accompanying veins and cephalic vein. We provide guidance on the selection and modification of free flaps to achieve the greatest function and cosmetic outcomes in the vessel depleted neck. Our collection of advanced management techniques will provide surgeons with more options to manage the complexity of the vessel depleted neck, and to further help patients understand the risk and benefits of these selections.