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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Development and validation of self-monitoring auto-updating prognostic models of survival for hospitalized COVID-19 patients.

Clinical prognostic models can assist patient care decisions. However, their performance can drift over time and location, necessitating model monitoring and updating. Despite rapid and significant changes during the pandemic, prognostic models for COVID-19 patients do not currently account for these drifts. We develop a framework for continuously monitoring and updating prognostic models and apply it to predict 28-day survival in COVID-19 patients. We use demographic, laboratory, and clinical data from electronic health records of 34912 hospitalized COVID-19 patients from March 2020 until May 2022 and compare three modeling methods. Model calibration performance drift is immediately detected with minor fluctuations in discrimination. The overall calibration on the prospective validation cohort is significantly improved when comparing the dynamically updated models against their static counterparts. Our findings suggest that, using this framework, models remain accurate and well-calibrated across various waves, variants, race and sex and yield positive net-benefits.

High Frequency of COVID-19 Vaccine Hesitancy among Canadians Immunized for Influenza: A Cross-Sectional Survey.

We assessed the frequency and correlates of COVID-19 vaccine hesitancy before Canada's vaccine rollout. A cross-sectional vaccine hesitancy survey was completed by consecutive patients/family members/staff who received the influenza vaccine at McGill University affiliated hospitals. Based on the self-reported likelihood of receiving a future vaccine (scale 0-10), the following three groups were defined: non-hesitant (score 10), mildly hesitant (7.1-9.9), and significantly hesitant (0-7). Factors associated with vaccine hesitancy were assessed with multivariate logistic regression analyses and binomial logistic regression machine learning modelling. The survey was completed by 1793 people. Thirty-seven percent of participants (n = 669) were hesitant (mildly: 315 (17.6%); significantly: 354 (19.7%)). Lower education levels, opposition and uncertainty about vaccines being mandatory, feelings of not receiving enough information about COVID-19 prevention, perceived social pressure to get a future vaccine, vaccine safety concerns, uncertainty regarding the vaccine risk-benefit ratio, and distrust towards pharmaceutical companies were factors associated with vaccine hesitancy. Vaccine safety concerns and opposition to mandatory vaccinations were the strongest correlates of vaccine hesitancy in both the logistic regressions and the machine learning model. In conclusion, in this study, over a third of people immunized for influenza before the COVID-19 vaccine rollout expressed some degree of vaccine hesitancy. Effectively addressing COVID-19 vaccine safety concerns may enhance vaccine uptake.

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.

Understanding Mental Health Needs and Gathering Feedback on Transcutaneous Auricular Vagus Nerve Stimulation as a Potential PTSD Treatment among 9/11 Responders Living with PTSD Symptoms 20 Years Later: A Qualitative Approach.

Posttraumatic stress disorder (PTSD) remains one of the most prevalent diagnoses of World Trade Center (WTC) 9/11 responders. Transcutaneous auricular vagus nerve stimulation (taVNS) is a potential treatment for PTSD, as it can downregulate activity in the brain, which is known to be related to stress responses and hyperarousal. To understand barriers and facilitators to engagement in mental health care and the feasibility and acceptability of using the taVNS device as a treatment for PTSD symptoms, a focus group was conducted among patients from the Queens WTC Health Program who had elevated symptoms of PTSD. The focus group discussion was recorded, transcribed, and analyzed. Three themes and subthemes emerged: (1) the continued prevalence of mental health difficulties and systematic challenges to accessing care; (2) positive reception toward the taVNS device as a potential treatment option, including a discussion of how to increase usability; and (3) feedback on increasing the feasibility and acceptance of the research methodology associated with testing the device in a pilot clinical trial. The findings highlight the need for additional treatment options to reduce PTSD symptoms in this population and provide key formative phase input for the pilot clinical trial of taVNS.

A fully implantable wireless bidirectional neuromodulation system for mice.

Novel research in the field of bioelectronic medicine requires neuromodulation systems that pair high-performance neurostimulation and bio-signal acquisition hardware with advanced signal processing and control algorithms. Although mice are the most commonly used animal in medical research, the size, weight, and power requirements of such bioelectronic systems either preclude use in mice or impose significant constraints on experimental design. Here, a fully-implantable recording and stimulation neuromodulation system suitable for use in mice is presented, measuring 2.2 cm3 and weighing 2.8 g. The bidirectional wireless interface allows simultaneous readout of multiple physiological signals and complete control over stimulation parameters, and a wirelessly rechargeable battery provides a lifetime of up to 5 days on a single charge. The device was implanted to deliver vagus nerve stimulation (n = 12 animals) and a functional neural interface (capable of inducing acute bradycardia) was demonstrated with lifetimes exceeding three weeks. The design utilizes only commercially-available electrical components and 3D-printed packaging, with the goal of facilitating widespread adoption and accelerating discovery and translation of future bioelectronic therapeutics.

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.

A method to quantify autonomic nervous system function in healthy, able-bodied individuals.

BACKGROUND: The autonomic nervous system (ANS) maintains physiological homeostasis in various organ systems via parasympathetic and sympathetic branches. ANS function is altered in common diffuse and focal conditions and heralds the beginning of environmental and disease stresses. Reliable, sensitive, and quantitative biomarkers, first defined in healthy participants, could discriminate among clinically useful changes in ANS function. This framework combines controlled autonomic testing with feature extraction during physiological responses. METHODS: Twenty-one individuals were assessed in two morning and two afternoon sessions over two weeks. Each session included five standard clinical tests probing autonomic function: squat test, cold pressor test, diving reflex test, deep breathing, and Valsalva maneuver. Noninvasive sensors captured continuous electrocardiography, blood pressure, breathing, electrodermal activity, and pupil diameter. Heart rate, heart rate variability, mean arterial pressure, electrodermal activity, and pupil diameter responses to the perturbations were extracted, and averages across participants were computed. A template matching algorithm calculated scaling and stretching features that optimally fit the average to an individual response. These features were grouped based on test and modality to derive sympathetic and parasympathetic indices for this healthy population. RESULTS: A significant positive correlation (p = 0.000377) was found between sympathetic amplitude response and body mass index. Additionally, longer duration and larger amplitude sympathetic and longer duration parasympathetic responses occurred in afternoon testing sessions; larger amplitude parasympathetic responses occurred in morning sessions. CONCLUSIONS: These results demonstrate the robustness and sensitivity of an algorithmic approach to extract multimodal responses from standard tests. This novel method of quantifying ANS function can be used for early diagnosis, measurement of disease progression, or treatment evaluation. TRIAL REGISTRATION: This study registered with Clinicaltrials.gov , identifier NCT04100486 . Registered September 24, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04100486 .