Gene targeting in amyotrophic lateral sclerosis using causality-based feature selection and machine learning.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare progressive neurodegenerative disease that affects upper and lower motor neurons. As the molecular basis of the disease is still elusive, the development of high-throughput sequencing technologies, combined with data mining techniques and machine learning methods, could provide remarkable results in identifying pathogenetic mechanisms. High dimensionality is a major problem when applying machine learning techniques in biomedical data analysis, since a huge number of features is available for a limited number of samples. The aim of this study was to develop a methodology for training interpretable machine learning models in the classification of ALS and ALS-subtypes samples, using gene expression datasets. METHODS: We performed dimensionality reduction in gene expression data using a semi-automated preprocessing systematic gene selection procedure using Statistically Equivalent Signature (SES), a causality-based feature selection algorithm, followed by Boosted Regression Trees (XGBoost) and Random Forest to train the machine learning classifiers. The SHapley Additive exPlanations (SHAP values) were used for interpretation of the machine learning classifiers. The methodology was developed and tested using two distinct publicly available ALS RNA-seq datasets. We evaluated the performance of SES as a dimensionality reduction method against: (a) Least Absolute Shrinkage and Selection Operator (LASSO), and (b) Local Outlier Factor (LOF). RESULTS: The proposed methodology achieved 85.18% accuracy for the classification of cerebellum or frontal cortex samples as C9orf72-related familial ALS, sporadic ALS or healthy samples. Importantly, the genes identified as the most determinative have also been reported as disease-associated in ALS literature. When tested in the evaluation dataset, the methodology achieved 88.89% accuracy for the classification of sporadic ALS motor neuron samples. When LASSO was used as feature selection method instead of SES, the accuracy of the machine learning classifiers ranged from 74.07 to 96.30%, depending on tissue assessed, while LOF underperformed significantly (77.78% accuracy for the classification of pooled cerebellum and frontal cortex samples). CONCLUSIONS: Using SES, we addressed the challenge of high dimensionality in gene expression data analysis, and we trained accurate machine learning ALS classifiers, specific for the gene expression patterns of different disease subtypes and tissue samples, while identifying disease-associated genes.

Application of a Machine Learning Algorithm to Develop and Validate a Prediction Model for Ambulatory Non-Arrivals.

BACKGROUND: Non-arrivals to scheduled ambulatory visits are common and lead to a discontinuity of care, poor health outcomes, and increased subsequent healthcare utilization. Reducing non-arrivals is important given their association with poorer health outcomes and cost to health systems. OBJECTIVE: To develop and validate a prediction model for ambulatory non-arrivals. DESIGN: Retrospective cohort study. PATIENTS OR SUBJECTS: Patients at an integrated health system who had an outpatient visit scheduled from January 1, 2020, to February 28, 2022. MAIN MEASURES: Non-arrivals to scheduled appointments. KEY RESULTS: There were over 4.3 million ambulatory appointments from 1.2 million adult patients. Patients with appointment non-arrivals were more likely to be single, racial/ethnic minorities, and not having an established primary care provider compared to those who arrived at their appointments. A prediction model using the XGBoost machine learning algorithm had the highest AUC value (0.768 [0.767-0.770]). Using SHAP values, the most impactful features in the model include rescheduled appointments, lead time (number of days from scheduled to appointment date), appointment provider, number of days since last appointment with the same department, and a patient's prior appointment status within the same department. Scheduling visits close to an appointment date is predicted to be less likely to result in a non-arrival. Overall, the prediction model calibrated well for each department, especially over the operationally relevant probability range of 0 to 40%. Departments with fewer observations and lower non-arrival rates generally had a worse calibration. CONCLUSIONS: Using a machine learning algorithm, we developed a prediction model for non-arrivals to scheduled ambulatory appointments usable for all medical specialties. The proposed prediction model can be deployed within an electronic health system or integrated into other dashboards to reduce non-arrivals. Future work will focus on the implementation and application of the model to reduce non-arrivals.

Prognostic models for COVID-19 needed updating to warrant transportability over time and space.

BACKGROUND: Supporting decisions for patients who present to the emergency department (ED) with COVID-19 requires accurate prognostication. We aimed to evaluate prognostic models for predicting outcomes in hospitalized patients with COVID-19, in different locations and across time. METHODS: We included patients who presented to the ED with suspected COVID-19 and were admitted to 12 hospitals in the New York City (NYC) area and 4 large Dutch hospitals. We used second-wave patients who presented between September and December 2020 (2137 and 3252 in NYC and the Netherlands, respectively) to evaluate models that were developed on first-wave patients who presented between March and August 2020 (12,163 and 5831). We evaluated two prognostic models for in-hospital death: The Northwell COVID-19 Survival (NOCOS) model was developed on NYC data and the COVID Outcome Prediction in the Emergency Department (COPE) model was developed on Dutch data. These models were validated on subsequent second-wave data at the same site (temporal validation) and at the other site (geographic validation). We assessed model performance by the Area Under the receiver operating characteristic Curve (AUC), by the E-statistic, and by net benefit. RESULTS: Twenty-eight-day mortality was considerably higher in the NYC first-wave data (21.0%), compared to the second-wave (10.1%) and the Dutch data (first wave 10.8%; second wave 10.0%). COPE discriminated well at temporal validation (AUC 0.82), with excellent calibration (E-statistic 0.8%). At geographic validation, discrimination was satisfactory (AUC 0.78), but with moderate over-prediction of mortality risk, particularly in higher-risk patients (E-statistic 2.9%). While discrimination was adequate when NOCOS was tested on second-wave NYC data (AUC 0.77), NOCOS systematically overestimated the mortality risk (E-statistic 5.1%). Discrimination in the Dutch data was good (AUC 0.81), but with over-prediction of risk, particularly in lower-risk patients (E-statistic 4.0%). Recalibration of COPE and NOCOS led to limited net benefit improvement in Dutch data, but to substantial net benefit improvement in NYC data. CONCLUSIONS: NOCOS performed moderately worse than COPE, probably reflecting unique aspects of the early pandemic in NYC. Frequent updating of prognostic models is likely to be required for transportability over time and space during a dynamic pandemic.

Efficacy of continuous monitoring of maternal temperature during labor using wireless axillary sensors.

Neonatal early onset sepsis (EOS) occurs in 0.5-0.8/1000 live births and is a major cause of morbidity and mortality. Its presenting signs in newborns are non-specific, so risk assessment before birth is essential. Maternal fever during labor is the strongest predictor of EOS, but the current standard is for infrequent manual determinations of temperature. We aimed to determine whether continuous measurement of temperature during labor is feasible, accurate, and more effective than manual measurements for detecting fever. Women were recruited on admission in labor at > 35 weeks gestational age, with < 6 cm cervical dilation. Sensors were affixed in the axilla, which transmitted every 4 minutes by Bluetooth to a dedicated tablet. Conventional temperature measurements were taken every 3-6 hours per routine. Of 336 subjects recruited, 155 had both > 4 hours of continuous data and > 2 manual temperature measurements and were included for analysis. Continuous recordings were feasible and correlated well with manual measurements independent of mean temperature. Of 15 episodes of fever > 38 °C detected by both methods, 13 were detected earlier by continuous (9 of those more than 1 hour earlier). Manual measurements missed 32 fevers > 38 °C and 13 fevers > 38.5 °C that were identified by continuous. Continuous measurement of maternal temperature for the duration of labor is practical and accurate. It may be more sensitive for identifying infants at risk for EOS than the current practice, enabling earlier and more effective targeted treatment of affected infants.

Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial.

OBJECTIVES: Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS: 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS: taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION: taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.

Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity.

The nervous system maintains physiological homeostasis through reflex pathways that modulate organ function. This process begins when changes in the internal milieu (e.g., blood pressure, temperature, or pH) activate visceral sensory neurons that transmit action potentials along the vagus nerve to the brainstem. IL-1ß and TNF, inflammatory cytokines produced by immune cells during infection and injury, and other inflammatory mediators have been implicated in activating sensory action potentials in the vagus nerve. However, it remains unclear whether neural responses encode cytokine-specific information. Here we develop methods to isolate and decode specific neural signals to discriminate between two different cytokines. Nerve impulses recorded from the vagus nerve of mice exposed to IL-1ß and TNF were sorted into groups based on their shape and amplitude, and their respective firing rates were computed. This revealed sensory neural groups responding specifically to TNF and IL-1ß in a dose-dependent manner. These cytokine-mediated responses were subsequently decoded using a Naive Bayes algorithm that discriminated between no exposure and exposures to IL-1ß and TNF (mean successful identification rate 82.9 ± 17.8%, chance level 33%). Recordings obtained in IL-1 receptor-KO mice were devoid of IL-1ß-related signals but retained their responses to TNF. Genetic ablation of TRPV1 neurons attenuated the vagus neural signals mediated by IL-1ß, and distal lidocaine nerve block attenuated all vagus neural signals recorded. The results obtained in this study using the methodological framework suggest that cytokine-specific information is present in sensory neural signals within the vagus nerve.

A Machine Learning Prediction Model of Respiratory Failure Within 48 Hours of Patient Admission for COVID-19: Model Development and Validation.

BACKGROUND: Predicting early respiratory failure due to COVID-19 can help triage patients to higher levels of care, allocate scarce resources, and reduce morbidity and mortality by appropriately monitoring and treating the patients at greatest risk for deterioration. Given the complexity of COVID-19, machine learning approaches may support clinical decision making for patients with this disease. OBJECTIVE: Our objective is to derive a machine learning model that predicts respiratory failure within 48 hours of admission based on data from the emergency department. METHODS: Data were collected from patients with COVID-19 who were admitted to Northwell Health acute care hospitals and were discharged, died, or spent a minimum of 48 hours in the hospital between March 1 and May 11, 2020. Of 11,525 patients, 933 (8.1%) were placed on invasive mechanical ventilation within 48 hours of admission. Variables used by the models included clinical and laboratory data commonly collected in the emergency department. We trained and validated three predictive models (two based on XGBoost and one that used logistic regression) using cross-hospital validation. We compared model performance among all three models as well as an established early warning score (Modified Early Warning Score) using receiver operating characteristic curves, precision-recall curves, and other metrics. RESULTS: The XGBoost model had the highest mean accuracy (0.919; area under the curve=0.77), outperforming the other two models as well as the Modified Early Warning Score. Important predictor variables included the type of oxygen delivery used in the emergency department, patient age, Emergency Severity Index level, respiratory rate, serum lactate, and demographic characteristics. CONCLUSIONS: The XGBoost model had high predictive accuracy, outperforming other early warning scores. The clinical plausibility and predictive ability of XGBoost suggest that the model could be used to predict 48-hour respiratory failure in admitted patients with COVID-19.

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.

Importance: There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). Objective: To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Design, Setting, and Participants: Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Exposures: Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Main Outcomes and Measures: Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. Results: A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). Conclusions and Relevance: This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.

Mechanisms of Saccadic Suppression in Primate Cortical Area V4.

UNLABELLED: Psychophysical studies have shown that subjects are often unaware of visual stimuli presented around the time of an eye movement. This saccadic suppression is thought to be a mechanism for maintaining perceptual stability. The brain might accomplish saccadic suppression by reducing the gain of visual responses to specific stimuli or by simply suppressing firing uniformly for all stimuli. Moreover, the suppression might be identical across the visual field or concentrated at specific points. To evaluate these possibilities, we recorded from individual neurons in cortical area V4 of nonhuman primates trained to execute saccadic eye movements. We found that both modes of suppression were evident in the visual responses of these neurons and that the two modes showed different spatial and temporal profiles: while gain changes started earlier and were more widely distributed across visual space, nonspecific suppression was found more often in the peripheral visual field, after the completion of the saccade. Peripheral suppression was also associated with increased noise correlations and stronger local field potential oscillations in the α frequency band. This pattern of results suggests that saccadic suppression shares some of the circuitry responsible for allocating voluntary attention. SIGNIFICANCE STATEMENT: We explore our surroundings by looking at things, but each eye movement that we make causes an abrupt shift of the visual input. Why doesn't the world look like a film recorded on a shaky camera? The answer in part is a brain mechanism called saccadic suppression, which reduces the responses of visual neurons around the time of each eye movement. Here we reveal several new properties of the underlying mechanisms. First, the suppression operates differently in the central and peripheral visual fields. Second, it appears to be controlled by oscillations in the local field potentials at frequencies traditionally associated with attention. These results suggest that saccadic suppression shares the brain circuits responsible for actively ignoring irrelevant stimuli.

Longitudinal dynamic clinical phenotypes of in-hospital COVID-19 patients across three dominant virus variants in New York.

BACKGROUND: COVID-19 is a challenging disease to characterize given its wide-ranging heterogeneous symptomatology. Several studies have attempted to extract clinical phenotypes but often relied on data from small patient cohorts, usually limited to only one viral variant and utilizing a static snapshot of patient data. OBJECTIVE: This study aimed to identify clinical phenotypes of hospitalized COVID-19 patients and investigate their longitudinal dynamics throughout the pandemic, with the goal to relate these phenotypes to clinical outcomes and treatment strategies. METHODS: We utilized routinely collected demographic and clinical data throughout the hospitalization of 38,077 patients admitted between 3/2020 to 5/2022, in 12 New York hospitals. Uniform Manifold Approximation and Projection and agglomerative hierarchical clustering were used to derive the clusters, followed by exploratory data analysis to compare the prevalence of comorbidities and treatments per cluster. RESULTS: 4 distinct clinical phenotypes remained robust in multi-site validation and were associated with different mortality rates. The temporal progression of these phenotypes throughout the COVID-19 pandemic demonstrated increased variability across the waves of the three dominant viral variants (alpha, delta, omicron). Longitudinal analysis evaluating changes in clinical phenotypes of each patient throughout the course of a 4-week hospital stay exemplified the dynamic nature of the disease progression. Factors such as sex, race/ethnicity and specific treatment modalities revealed significant and clinically relevant differences between the observed phenotypes. CONCLUSIONS: Our proposed methodology has the potential of enabling clinicians and policy makers to draw evidence-based conclusions for guiding treatment modalities in a dynamic fashion.

Factors associated with immune responses to SARS-CoV-2 vaccination in autoimmune disease individuals.

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 autoimmune subjects, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted multiple sclerosis (MS) subjects were associated with higher CD8 T cell responses. By contrast, subjects taking mycophenolate mofetil exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low IgG anti-spike response included B cell depletion within the last year, fingolimod, and combination treatment with mycophenolate mofetil (MMF) and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine, is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of pre-existing anti-type I interferon antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.

The association of clinically relevant variables with chest radiograph lung disease burden quantified in real-time by radiologists upon initial presentation in individuals hospitalized with COVID-19.

OBJECTIVES: We aimed to correlate lung disease burden on presentation chest radiographs (CXR), quantified at the time of study interpretation, with clinical presentation in patients hospitalized with coronavirus disease 2019 (COVID-19). MATERIAL AND METHODS: This retrospective cross-sectional study included 5833 consecutive adult patients, aged 18 and older, hospitalized with a diagnosis of COVID-19 with a CXR quantified in real-time while hospitalized in 1 of 12 acute care hospitals across a multihospital integrated healthcare network between March 24, 2020, and May 22, 2020. Lung disease burden was quantified in real-time by 118 radiologists on 5833 CXR at the time of exam interpretation with each lung annotated by the degree of lung opacity as clear (0%), mild (1-33%), moderate (34-66%), or severe (67-100%). CXR findings were classified as (1) clear versus disease, (2) unilateral versus bilateral, (3) symmetric versus asymmetric, or (4) not severe versus severe. Lung disease burden was characterized on initial presentation by patient demographics, co-morbidities, vital signs, and lab results with chi-square used for univariate analysis and logistic regression for multivariable analysis. RESULTS: Patients with severe lung disease were more likely to have oxygen impairment, an elevated respiratory rate, low albumin, high lactate dehydrogenase, and high ferritin compared to non-severe lung disease. A lack of opacities in COVID-19 was associated with a low estimated glomerular filtration rate, hypernatremia, and hypoglycemia. CONCLUSIONS: COVID-19 lung disease burden quantified in real-time on presentation CXR was characterized by demographics, comorbidities, emergency severity index, Charlson Comorbidity Index, vital signs, and lab results on 5833 patients. This novel approach to real-time quantified chest radiograph lung disease burden by radiologists needs further research to understand how this information can be incorporated to improve clinical care for pulmonary-related diseases.. An absence of opacities in COVID-19 may be associated with poor oral intake and a prerenal state as evidenced by the association of clear CXRs with a low eGFR, hypernatremia, and hypoglycemia.

Prediction of intrapartum fever using continuously monitored vital signs and heart rate variability.

Objectives: Neonatal early onset sepsis (EOS), bacterial infection during the first seven days of life, is difficult to diagnose because presenting signs are non-specific, but early diagnosis before birth can direct life-saving treatment for mother and baby. Specifically, maternal fever during labor from placental infection is the strongest predictor of EOS. Alterations in maternal heart rate variability (HRV) may precede development of intrapartum fever, enabling incipient EOS detection. The objective of this work was to build a predictive model for intrapartum fever. Methods: Continuously measured temperature, heart rate, and beat-to-beat RR intervals were obtained from wireless sensors on women (n = 141) in labor; traditional manual vital signs were taken every 3-6 hours. Validated measures of HRV were calculated in moving 5-minute windows of RR intervals: standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive differences (RMSSD) between normal heartbeats. Results: Fever (>38.0 °C) was detected by manual or continuous measurements in 48 women. Compared to afebrile mothers, average SDNN and RMSSD in febrile mothers decreased significantly (p < 0.001) at 2 and 3 hours before fever onset, respectively. This observed HRV divergence and raw recorded vitals were applied to a logistic regression model at various time horizons, up to 4-5 hours before fever onset. Model performance increased with decreasing time horizons, and a model built using continuous vital signs as input variables consistently outperformed a model built from episodic vital signs. Conclusions: HRV-based predictive models could identify mothers at risk for fever and infants at risk for EOS, guiding maternal antibiotic prophylaxis and neonatal monitoring.

A radiographic, deep transfer learning framework, adapted to estimate lung opacities from chest x-rays.

Chest radiographs (CXRs) are the most widely available radiographic imaging modality used to detect respiratory diseases that result in lung opacities. CXR reports often use non-standardized language that result in subjective, qualitative, and non-reproducible opacity estimates. Our goal was to develop a robust deep transfer learning framework and adapt it to estimate the degree of lung opacity from CXRs. Following CXR data selection based on exclusion criteria, segmentation schemes were used for ROI (Region Of Interest) extraction, and all combinations of segmentation, data balancing, and classification methods were tested to pick the top performing models. Multifold cross validation was used to determine the best model from the initial selected top models, based on appropriate performance metrics, as well as a novel Macro-Averaged Heatmap Concordance Score (MA HCS). Performance of the best model is compared against that of expert physician annotators, and heatmaps were produced. Finally, model performance sensitivity analysis across patient populations of interest was performed. The proposed framework was adapted to the specific use case of estimation of degree of CXR lung opacity using ordinal multiclass classification. Acquired between March 24, 2020, and May 22, 2020, 38,365 prospectively annotated CXRs from 17,418 patients were used. We tested three neural network architectures (ResNet-50, VGG-16, and ChexNet), three segmentation schemes (no segmentation, lung segmentation, and lateral segmentation based on spine detection), and three data balancing strategies (undersampling, double-stage sampling, and synthetic minority oversampling) using 38,079 CXR images for training, and validation with 286 images as the out-of-the-box dataset that underwent expert radiologist adjudication. Based on the results of these experiments, the ResNet-50 model with undersampling and no ROI segmentation is recommended for lung opacity classification, based on optimal values for the MAE metric and HCS (Heatmap Concordance Score). The degree of agreement between the opacity scores predicted by this model with respect to the two sets of radiologist scores (OR or Original Reader and OOBTR or Out Of Box Reader) in terms of performance metrics is superior to the inter-radiologist opacity score agreement.

Calcium imaging and analysis of the jugular-nodose ganglia enables identification of distinct vagal sensory neuron subsets.

Objective.Sensory nerves of the peripheral nervous system (PNS) transmit afferent signals from the body to the brain. These peripheral nerves are composed of distinct subsets of fibers and associated cell bodies, which reside in peripheral ganglia distributed throughout the viscera and along the spinal cord. The vagus nerve (cranial nerve X) is a complex polymodal nerve that transmits a wide array of sensory information, including signals related to mechanical, chemical, and noxious stimuli. To understand how stimuli applied to the vagus nerve are encoded by vagal sensory neurons in the jugular-nodose ganglia, we developed a framework for micro-endoscopic calcium imaging and analysis.Approach.We developed novel methods forin vivoimaging of the intact jugular-nodose ganglion using a miniature microscope (Miniscope) in transgenic mice with the genetically-encoded calcium indicator GCaMP6f. We adapted the Python-based analysis package Calcium Imaging Analysis (CaImAn) to process the resulting one-photon fluorescence data into calcium transients for subsequent analysis. Random forest classification was then used to identify specific types of neuronal responders.Results.We demonstrate that recordings from the jugular-nodose ganglia can be accomplished through careful surgical dissection and ganglia stabilization. Using a customized acquisition and analysis pipeline, we show that subsets of vagal sensory neurons respond to different chemical stimuli applied to the vagus nerve. Successful classification of the responses with a random forest model indicates that certain calcium transient features, such as amplitude and duration, are important for encoding these stimuli by sensory neurons.Significance.This experimental approach presents a new framework for investigating how individual vagal sensory neurons encode various stimuli on the vagus nerve. Our surgical and analytical approach can be applied to other PNS ganglia in rodents and other small animal species to elucidate previously unexplored roles for peripheral neurons in a diverse set of physiological functions.

The Fifth Bioelectronic Medicine Summit: today's tools, tomorrow's therapies.

The emerging field of bioelectronic medicine (BEM) is poised to make a significant impact on the treatment of several neurological and inflammatory disorders. With several BEM therapies being recently approved for clinical use and others in late-phase clinical trials, the 2022 BEM summit was a timely scientific meeting convening a wide range of experts to discuss the latest developments in the field. The BEM Summit was held over two days in New York with more than thirty-five invited speakers and panelists comprised of researchers and experts from both academia and industry. The goal of the meeting was to bring international leaders together to discuss advances and cultivate collaborations in this emerging field that incorporates aspects of neuroscience, physiology, molecular medicine, engineering, and technology. This Meeting Report recaps the latest findings discussed at the Meeting and summarizes the main developments in this rapidly advancing interdisciplinary field. Our hope is that this Meeting Report will encourage researchers from academia and industry to push the field forward and generate new multidisciplinary collaborations that will form the basis of new discoveries that we can discuss at the next BEM Summit.

US and Dutch Perspectives on the Use of COVID-19 Clinical Prediction Models: Findings from a Qualitative Analysis.

INTRODUCTION: Clinical prediction models (CPMs) for coronavirus disease 2019 (COVID-19) may support clinical decision making, treatment, and communication. However, attitudes about using CPMs for COVID-19 decision making are unknown. METHODS: Online focus groups and interviews were conducted among health care providers, survivors of COVID-19, and surrogates (i.e., loved ones/surrogate decision makers) in the United States and the Netherlands. Semistructured questions explored experiences about clinical decision making in COVID-19 care and facilitators and barriers for implementing CPMs. RESULTS: In the United States, we conducted 4 online focus groups with 1) providers and 2) surrogates and survivors of COVID-19 between January 2021 and July 2021. In the Netherlands, we conducted 3 focus groups and 4 individual interviews with 1) providers and 2) surrogates and survivors of COVID-19 between May 2021 and July 2021. Providers expressed concern about CPM validity and the belief that patients may interpret CPM predictions as absolute. They described CPMs as potentially useful for resource allocation, triaging, education, and research. Several surrogates and people who had COVID-19 were not given prognostic estimates but believed this information would have supported and influenced their decision making. A limited number of participants felt the data would not have applied to them and that they or their loved ones may not have survived, as poor prognosis may have suggested withdrawal of treatment. CONCLUSIONS: Many providers had reservations about using CPMs for people with COVID-19 due to concerns about CPM validity and patient-level interpretation of the outcome predictions. However, several people who survived COVID-19 and their surrogates indicated that they would have found this information useful for decision making. Therefore, information provision may be needed to improve provider-level comfort and patient and surrogate understanding of CPMs. HIGHLIGHTS: While clinical prediction models (CPMs) may provide an objective means of assessing COVID-19 prognosis, provider concerns about CPM validity and the interpretation of CPM predictions may limit their clinical use.Providers felt that CPMs may be most useful for resource allocation, triage, research, or educational purposes for COVID-19.Several survivors of COVID-19 and their surrogates felt that CPMs would have been informative and may have aided them in making COVID-19 treatment decisions, while others felt the data would not have applied to them.

Organ- and function-specific anatomical organization of vagal fibers supports fascicular vagus nerve stimulation.

Vagal fibers travel inside fascicles and form branches to innervate organs and regulate organ functions. Existing vagus nerve stimulation (VNS) therapies activate vagal fibers non-selectively, often resulting in reduced efficacy and side effects from non-targeted organs. The transverse and longitudinal arrangement of fibers inside the vagal trunk with respect to the functions they mediate and organs they innervate is unknown, however it is crucial for selective VNS. Using micro-computed tomography imaging, we tracked fascicular trajectories and found that, in swine, sensory and motor fascicles are spatially separated cephalad, close to the nodose ganglion, and merge caudad, towards the lower cervical and upper thoracic region; larynx-, heart- and lung-specific fascicles are separated caudad and progressively merge cephalad. Using quantified immunohistochemistry at single fiber level, we identified and characterized all vagal fibers and found that fibers of different morphological types are differentially distributed in fascicles: myelinated afferents and efferents occupy separate fascicles, myelinated and unmyelinated efferents also occupy separate fascicles, and small unmyelinated afferents are widely distributed within most fascicles. We developed a multi-contact cuff electrode to accommodate the fascicular structure of the vagal trunk and used it to deliver fascicle-selective cervical VNS in anesthetized and awake swine. Compound action potentials from distinct fiber types, and physiological responses from different organs, including laryngeal muscle, cough, breathing, and heart rate responses are elicited in a radially asymmetric manner, with consistent angular separations that agree with the documented fascicular organization. These results indicate that fibers in the trunk of the vagus nerve are anatomically organized according to functions they mediate and organs they innervate and can be asymmetrically activated by fascicular cervical VNS.

Relationships between spike-free local field potentials and spike timing in human temporal cortex.

Intracortical recordings comprise both fast events, action potentials (APs), and slower events, known as local field potentials (LFPs). Although it is believed that LFPs mostly reflect local synaptic activity, it is unclear which of their signal components are most closely related to synaptic potentials and would therefore be causally related to the occurrence of individual APs. This issue is complicated by the significant contribution from AP waveforms, especially at higher LFP frequencies. In recordings of single-cell activity and LFPs from the human temporal cortex, we computed quantitative, nonlinear, causal dynamic models for the prediction of AP timing from LFPs, at millisecond resolution, before and after removing AP contributions to the LFP. In many cases, the timing of a significant number of single APs could be predicted from spike-free LFPs at different frequencies. Not surprisingly, model performance was superior when spikes were not removed. Cells whose activity was predicted by the spike-free LFP models generally fell into one of two groups: in the first group, neuronal spike activity was associated with specific phases of low LFP frequencies, lower spike activity at high LFP frequencies, and a stronger linear component in the spike-LFP model; in the second group, neuronal spike activity was associated with larger amplitude of high LFP frequencies, less frequent phase locking, and a stronger nonlinear model component. Spike timing in the first group was better predicted by the sign and level of the LFP preceding the spike, whereas spike timing in the second group was better predicted by LFP power during a certain time window before the spike.

Long-range cortical synchronization supports abrupt visual learning.

Visual plasticity declines sharply after the critical period, yet we easily learn to recognize new faces and places, even as adults. Such learning is often characterized by a "moment of insight," an abrupt and dramatic improvement in recognition. The mechanisms that support abrupt learning are unknown, but one hypothesis is that they involve changes in synchronization between brain regions. To test this hypothesis, we used a behavioral task in which non-human primates rapidly learned to recognize novel images and to associate them with specific responses. Simultaneous recordings from inferotemporal and prefrontal cortices revealed a transient synchronization of neural activity between these areas that peaked around the moment of insight. Synchronization was strongest between inferotemporal sites that encoded images and reward-sensitive prefrontal sites. Moreover, its magnitude intensified gradually over image exposures, suggesting that abrupt learning is the culmination of a search for informative signals within a circuit linking sensory information to task demands.