Understanding patterns of fatigue in health and disease: protocol for an ecological momentary assessment study using digital technologies.

INTRODUCTION: Fatigue is prevalent across a wide range of medical conditions and can be debilitating and distressing. It is likely that fatigue is experienced differently according to the underlying aetiology, but this is poorly understood. Digital health technologies present a promising approach to give new insights into fatigue.The aim of this study is to use digital health technologies, real-time self-reports and qualitative interview data to investigate how fatigue is experienced over time in participants with myeloma, long COVID, heart failure and in controls without problematic fatigue. Objectives are to understand which sensed parameters add value to the characterisation of fatigue and to determine whether study processes are feasible, acceptable and scalable. METHODS AND ANALYSIS: An ecological momentary assessment study will be carried out over 2 or 4 weeks (participant defined). Individuals with fatigue relating to myeloma (n=10), heart failure (n=10), long COVID (n=10) and controls without problematic fatigue or a study condition (n=10) will be recruited. ECG patches will measure heart rate variability, respiratory rate, body temperature, activity and posture. A wearable bracelet accompanied by environment beacons will measure physical activity, sleep and room location within the home. Self-reports of mental and physical fatigue will be collected via smartphone app four times daily and on-demand. Validated fatigue and affect questionnaires will be completed at baseline and at 2 weeks. End-of-study interviews will investigate experiences of fatigue and study participation. A feedback session will be offered to participants to discuss their data.Data will be analysed using multilevel modelling and machine learning. Interviews and feedback sessions will be analysed using content or thematic analyses. ETHICS AND DISSEMINATION: This study was approved by the East of England-Cambridge East Research Ethics Committee (22/EE/0261). The results will be disseminated in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: NCT05622669.

Machines, mathematics, and modules: the potential to provide real-time metrics for pain under anesthesia.

The brain-based assessments under anesthesia have provided the ability to evaluate pain/nociception during surgery and the potential to prevent long-term evolution of chronic pain. Prior studies have shown that the functional near-infrared spectroscopy (fNIRS)-measured changes in cortical regions such as the primary somatosensory and the polar frontal cortices show consistent response to evoked and ongoing pain in awake, sedated, and anesthetized patients. We take this basic approach and integrate it into a potential framework that could provide real-time measures of pain/nociception during the peri-surgical period. This application could have significant implications for providing analgesia during surgery, a practice that currently lacks quantitative evidence to guide patient tailored pain management. Through a simple readout of "pain" or "no pain," the proposed system could diminish or eliminate levels of intraoperative, early post-operative, and potentially, the transition to chronic post-surgical pain. The system, when validated, could also be applied to measures of analgesic efficacy in the clinic.

Relativistic Perturbation Theory for Black-Hole Boson Clouds.

We develop a relativistic perturbation theory for scalar clouds around rotating black holes. We first introduce a relativistic product and corresponding orthogonality relation between modes, extending a recent result for gravitational perturbations. We then derive the analog of time-dependent perturbation theory in quantum mechanics, and apply it to calculate self-gravitational frequency shifts. This approach supersedes the nonrelativistic "gravitational atom" approximation, brings close agreement with numerical relativity, and has practical applications for gravitational-wave astronomy.

A lamprey neural cell type atlas illuminates the origins of the vertebrate brain.

The vertebrate brain emerged more than ~500 million years ago in common evolutionary ancestors. To systematically trace its cellular and molecular origins, we established a spatially resolved cell type atlas of the entire brain of the sea lamprey-a jawless species whose phylogenetic position affords the reconstruction of ancestral vertebrate traits-based on extensive single-cell RNA-seq and in situ sequencing data. Comparisons of this atlas to neural data from the mouse and other jawed vertebrates unveiled various shared features that enabled the reconstruction of cell types, tissue structures and gene expression programs of the ancestral vertebrate brain. However, our analyses also revealed key tissues and cell types that arose later in evolution. For example, the ancestral brain was probably devoid of cerebellar cell types and oligodendrocytes (myelinating cells); our data suggest that the latter emerged from astrocyte-like evolutionary precursors in the jawed vertebrate lineage. Altogether, our work illuminates the cellular and molecular architecture of the ancestral vertebrate brain and provides a foundation for exploring its diversification during evolution.

Can pain under anesthesia be measured? Pain-related brain function using functional near-infrared spectroscopy during knee surgery.

Significance: Quantitative measurement of perisurgical brain function may provide insights into the processes contributing to acute and chronic postsurgical pain. Aim: We evaluate the hemodynamic changes in the prefrontal cortex (medial frontopolar cortex/mFPC and lateral prefrontal cortex) and the primary somatosensory cortex/S1 using functional near-infrared spectroscopy (fNIRS) in 18 patients (18.2±3.3 years, 11 females) undergoing knee arthroscopy. Approach: We examined the (a) hemodynamic response to surgery and (b) the relationship between surgery-modulated cortical connectivity (using beta-series correlation) and acute postoperative pain levels using Pearson's r correlation with 10,000 permutations. Results: We show a functional dissociation between mFPC and S1 in response to surgery, where mFPC deactivates, and S1 activates following a procedure. Furthermore, the connectivity between (a) left mFPC and right S1 (original r=-0.683, ppermutation=0.001), (b) right mFPC and right S1 (original r=-0.633, ppermutation=0.002), and (c) left mFPC and right S1 (original r=-0.695, ppermutation=0.0002) during surgery were negatively associated with acute postoperative pain levels. Conclusions: Our findings suggest that greater functional dissociation between mFPC and S1 is likely the result of inadequately controlled nociceptive barrage during surgery leading to more significant postoperative pain. It also supports the utility of fNIRS during the perioperative state for pain monitoring and patient risk assessment for chronic pain.

Neural Importance Sampling for Rapid and Reliable Gravitational-Wave Inference.

We combine amortized neural posterior estimation with importance sampling for fast and accurate gravitational-wave inference. We first generate a rapid proposal for the Bayesian posterior using neural networks, and then attach importance weights based on the underlying likelihood and prior. This provides (1) a corrected posterior free from network inaccuracies, (2) a performance diagnostic (the sample efficiency) for assessing the proposal and identifying failure cases, and (3) an unbiased estimate of the Bayesian evidence. By establishing this independent verification and correction mechanism we address some of the most frequent criticisms against deep learning for scientific inference. We carry out a large study analyzing 42 binary black hole mergers observed by LIGO and Virgo with the SEOBNRv4PHM and IMRPhenomXPHM waveform models. This shows a median sample efficiency of ≈10% (2 orders of magnitude better than standard samplers) as well as a tenfold reduction in the statistical uncertainty in the log evidence. Given these advantages, we expect a significant impact on gravitational-wave inference, and for this approach to serve as a paradigm for harnessing deep learning methods in scientific applications.

Evolution of a chordate-specific mechanism for myoblast fusion.

Vertebrate myoblast fusion allows for multinucleated muscle fibers to compound the size and strength of mononucleated cells, but the evolution of this important process is unknown. We investigated the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here, we report that Myomaker likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while Myomixer appears to have evolved de novo in early vertebrates. Functional tests revealed a complex evolutionary history of myoblast fusion. A prevertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Evolutionary comparisons between vertebrate and nonvertebrate Myomaker revealed key structural and mechanistic insights into myoblast fusion. Thus, our findings suggest an evolutionary model of chordate fusogens and illustrate how new genes shape the emergence of novel morphogenetic traits and mechanisms.

Measuring "pain load" during general anesthesia.

Introduction: Functional near-infrared spectroscopy (fNIRS) allows for ongoing measures of brain functions during surgery. The ability to evaluate cumulative effects of painful/nociceptive events under general anesthesia remains a challenge. Through observing signal differences and setting boundaries for when observed events are known to produce pain/nociception, a program can trigger when the concentration of oxygenated hemoglobin goes beyond ±0.3 mM from 25 s after standardization. Method: fNIRS signals were retrieved from patients undergoing knee surgery for anterior cruciate ligament repair under general anesthesia. Continuous fNIRS measures were measured from the primary somatosensory cortex (S1), which is known to be involved in evaluation of nociception, and the medial polar frontal cortex (mPFC), which are both involved in higher cortical functions (viz. cognition and emotion). Results: A ±0.3 mM threshold for painful/nociceptive events was observed during surgical incisions at least twice, forming a basis for a potential near-real-time recording of pain/nociceptive events. Evidence through observed true positives in S1 and true negatives in mPFC are linked through statistically significant correlations and this threshold. Conclusion: Our results show that standardizing and observing concentrations over 25 s using the ±0.3 mM threshold can be an arbiter of the continuous number of incisions performed on a patient, contributing to a potential intraoperative pain load index that correlates with post-operative levels of pain and potential pain chronification.

Brain-based measures of nociception during general anesthesia with remifentanil: A randomized controlled trial.

BACKGROUND: Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation. METHODS AND FINDINGS: We investigated the effects of continuous remifentanil on cortical hemodynamics during cardiac ablation under anesthesia. In a randomized, double-blinded, placebo (PL)-controlled trial, we examined 32 pediatric patients (mean age of 15.8 years,16 females) undergoing catheter ablation for cardiac arrhythmias at the Cardiology Department of Boston Children's Hospital from October 2016 to March 2020; 9 received 0.9% NaCl, 12 received low-dose (LD) remifentanil (0.25 mcg/kg/min), and 11 received high-dose (HD) remifentanil (0.5 mcg/kg/min). The hemodynamic changes of primary somatosensory and prefrontal cortices were recorded during surgery using a continuous wave fNIRS system. The primary outcome measures were the changes in oxyhemoglobin concentration (NadirHbO, i.e., lowest oxyhemoglobin concentration and PeakHbO, i.e., peak change and area under the curve) of medial frontopolar cortex (mFPC), lateral prefrontal cortex (lPFC) and primary somatosensory cortex (S1) to ablation in PL versus remifentanil groups. Secondary measures included the fNIRS response to an auditory control condition. The data analysis was performed on an intention-to-treat (ITT) basis. Remifentanil group (dosage subgroups combined) was compared with PL, and a post hoc analysis was performed to identify dose effects. There were no adverse events. The groups were comparable in age, sex, and number of ablations. Results comparing remifentanil versus PL show that PL group exhibit greater NadirHbO in inferior mFPC (mean difference (MD) = 1.229, 95% confidence interval [CI] = 0.334, 2.124, p < 0.001) and superior mFPC (MD = 1.206, 95% CI = 0.303, 2.109, p = 0.001) and greater PeakHbO in inferior mFPC (MD = -1.138, 95% CI = -2.062, -0.214, p = 0.002) and superior mFPC (MD = -0.999, 95% CI = -1.961, -0.036, p = 0.008) in response to ablation. S1 activation from ablation was greatest in PL, then LD, and HD groups, but failed to reach significance, whereas lPFC activation to ablation was similar in all groups. Ablation versus auditory stimuli resulted in higher PeakHbO in inferior mFPC (MD = 0.053, 95% CI = 0.004, 0.101, p = 0.004) and superior mFPC (MD = 0.052, 95% CI = 0.013, 0.091, p < 0.001) and higher NadirHbO in posterior superior S1 (Pos. SS1; MD = -0.342, 95% CI = -0.680, -0.004, p = 0.007) during ablation of all patients. Remifentanil group had smaller NadirHbO in inferior mFPC (MD = 0.098, 95% CI = 0.009, 0.130, p = 0.003) and superior mFPC (MD = 0.096, 95% CI = 0.008, 0.116, p = 0.003) and smaller PeakHbO in superior mFPC (MD = -0.092, 95% CI = -0.680, -0.004, p = 0.007) during both the stimuli. Study limitations were small sample size, motion from surgery, indirect measure of nociception, and shallow penetration depth of fNIRS only allowing access to superficial cortical layers. CONCLUSIONS: We observed cortical activity related to nociception during cardiac ablation under general anesthesia with remifentanil. It highlights the potential of fNIRS to provide an objective pain measure in unconscious patients, where cortical-based measures may be more accurate than current evaluation methods. Future research may expand on this application to produce a real-time indication of pain that will aid clinicians in providing immediate and adequate pain treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02703090.

fNIRS brain measures of ongoing nociception during surgical incisions under anesthesia.

Significance: Functional near-infrared spectroscopy (fNIRS) has evaluated pain in awake and anesthetized states. Aim: We evaluated fNIRS signals under general anesthesia in patients undergoing knee surgery for anterior cruciate ligament repair. Approach: Patients were split into groups: those with regional nerve block (NB) and those without (non-NB). Continuous fNIRS measures came from three regions: the primary somatosensory cortex (S1), known to be involved in evaluation of nociception, the lateral prefrontal cortex (BA9), and the polar frontal cortex (BA10), both involved in higher cortical functions (such as cognition and emotion). Results: Our results show three significant differences in fNIRS signals to incision procedures between groups: (1) NB compared with non-NB was associated with a greater net positive hemodynamic response to pain procedures in S1; (2) dynamic correlation between the prefrontal cortex (PreFC) and S1 within 1 min of painful procedures are anticorrelated in NB while positively correlated in non-NB; and (3) hemodynamic measures of activation were similar at two separate time points during surgery (i.e., first and last incisions) in PreFC and S1 but showed significant differences in their overlap. Comparing pain levels immediately after surgery and during discharge from postoperative care revealed no significant differences in the pain levels between NB and non-NB. Conclusion: Our data suggest multiple pain events that occur during surgery using devised algorithms could potentially give a measure of "pain load." This may allow for evaluation of central sensitization (i.e., a heightened state of the nervous system where noxious and non-noxious stimuli is perceived as painful) to postoperative pain levels and the resulting analgesic consumption. This evaluation could potentially predict postsurgical chronic neuropathic pain.

Initial Single-Center ST-Segment Elevation Myocardial Infarction Experience in New York Before and During the COVID-19 Pandemic.

BACKGROUND/PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a highly contagious and lethal virus, devastating healthcare systems throughout the world. Following a period of stability, the coronavirus disease 2019 (COVID-19) pandemic appears to be re-intensifying globally. As the virus continues to evolve, so does our understanding of its implications on ST-segment elevation myocardial infarction (STEMI). We sought to describe a single center STEMI experience at one of the epicenters during the COVID-19 pandemic. METHODS/MATERIALS: We conducted a retrospective, observational study comparing STEMI patients during the pandemic period (March 1 to August 31, 2020) to those with STEMI during the pre-pandemic period (March 1 to August 31, 2019) at NYU Langone Hospital - Long Island, a tertiary-care center in Nassau County, New York. Additionally, we describe our subset of COVID-19 patients with STEMI during the pandemic. RESULTS: The acute myocardial infarction (AMI) team was activated for 183 patients during both periods. There were a similar number of AMI team activations during the pandemic period (n = 93) compared to the pre-pandemic period (n = 90). Baseline characteristics did not differ during both periods; however, infection control measures and additional investigation were required to clarify the diagnosis during the pandemic, resulting in a signal toward longer door-to-balloon times (95.9 min vs. 74.4 min, p = 0.0587). We observed similar inpatient length of stay (LOS) (3.6 days vs. 5.0 days, p = 0.0901) and mortality (13.2% vs. 9.2%, p = 0.5876). There were 6 COVID-19-positive patients who presented with STEMI, of whom 4 were emergently taken to the cardiac catheterization laboratory with successful percutaneous coronary intervention (PCI) performed in 3 patients. The 2 patients who were not offered primary PCI expired, as both were treated medically, one with thrombolytics. CONCLUSIONS: Our single-center study, in New York, at one of the epicenters of the pandemic, demonstrated a similar number of AMI team activations, mimicking the seasonal variability seen in 2019, but with a signal toward longer door-to-balloon time. Despite this, inpatient LOS and mortality remained similar.

Towards a deeper understanding of pain: How machine learning and deep learning algorithms are needed to provide the next generation of pain medicine for use in the clinic.

As our definition of pain evolves, the factors implicit in defining and predicting pain status grow. These factors each have unique data characteristics and their outcomes each have unique target attributes. The clinical characterization of pain does not, as defined in the most recent IASP definition, require any tissue pathology, suggesting that the experience of pain can be uniquely psychological in nature. Predicting a persons pain status may be optimized through integration of multiple independent observations; however, how they are integrated has direct relevance towards predicting chronic pain development, clinical application, and research investigation. The current challenge is to find clinically-mindful ways of integrating clinical pain rating scales with neuroimaging of the peripheral and central nervous system with the biopsychocial environment and improving our capacity for diagnostic flexibility and knowledge translation through data modeling. This commentary addresses how our current knowledge of pain phenotypes and risk factors interacts with statistical models and how we can proceed forward in a clinically responsible way.

Migraine: interactions between brain's trait and state.

It is well established that migraine is a multifactorial disorder. A deep understanding of migraine should be based upon both the underlying traits and the current states affected by different physiological, psychological, and environmental factors. At this point, there is no framework fully meeting these criteria. Here, we describe a broader view of the migraine disorder defined as a dysfunctional brain state and trait interaction. In this model, we consider events that may enhance or diminish migraine responsivity based on an individual's trait and state. This could provide an expanded view for considering how migraine attacks are sometimes precipitated by "triggers" and sometimes not, how these factors only lead to migraine attacks in migraine patients, or how individuals with an increased risk for migraine do not show any symptoms at all. Summarizing recent studies and evidence that support the concept of migraine as a brain state-trait interaction can also contribute to improving patient care by highlighting the importance of precision medicine and applying measures that are able to capture how different traits and states work together to determine migraine.

Real-Time Gravitational Wave Science with Neural Posterior Estimation.

We demonstrate unprecedented accuracy for rapid gravitational wave parameter estimation with deep learning. Using neural networks as surrogates for Bayesian posterior distributions, we analyze eight gravitational wave events from the first LIGO-Virgo Gravitational-Wave Transient Catalog and find very close quantitative agreement with standard inference codes, but with inference times reduced from O(day) to 20 s per event. Our networks are trained using simulated data, including an estimate of the detector noise characteristics near the event. This encodes the signal and noise models within millions of neural-network parameters and enables inference for any observed data consistent with the training distribution, accounting for noise nonstationarity from event to event. Our algorithm-called "DINGO"-sets a new standard in fast and accurate inference of physical parameters of detected gravitational wave events, which should enable real-time data analysis without sacrificing accuracy.

Predictors and Outcome Impact of Mitral Regurgitation in Transcatheter Aortic Valve Replacement.

BACKGROUND/PURPOSE: Several studies have reported that mitral regurgitation (MR) can improve following transcatheter aortic valve replacement (TAVR) alone using earlier-generation valves. The purpose of this study was to determine the predictors and short-term outcome impact of MR in patients undergoing TAVR using all generation valves across all risk groups. METHODS/MATERIALS: In this retrospective, study from 2012 to 2020, we reviewed data on 1822 low-, intermediate-, and high-risk patients who underwent TAVR. Included were 1266 patients with baseline MR who underwent transfemoral TAVR. Our primary outcome was persistence or worsening of baseline MR post-TAVR. Additional endpoints included an inpatient composite (intensive care unit length of stay >24 h, post-TAVR length of stay >2 days, and inpatient death), 30-day composite (30-day death or readmission), and 1-year composite (1-year death or readmission). RESULTS: Of the 1266 patients included, 665 had significant baseline MR (≥moderate), which improved in 79.4% of patients (n=528). Female patients, those with lower body mass indices, and those with higher right ventricular systolic pressures were more likely to have persistence or worsening of baseline MR. Patients whose baseline MR persisted or worsened, had higher rates (80.3% vs. 77.3%, p=0.0019) of our inpatient composite, higher rates (15.3% vs. 10.0%, p=0.0389) of our 30-day composite, and higher rates (36.7% vs. 26.8%, p=0.0107) of our 1-year composite when compared to patients whose baseline MR improved post-TAVR. CONCLUSIONS: Our study identifies clinical characteristics, which help identify patients who may require closer post-procedural follow-up and warrant possible staged mitral valve intervention post-TAVR across all risk groups.

NIRS measures in pain and analgesia: Fundamentals, features, and function.

Current pain assessment techniques based only on clinical evaluation and self-reports are not objective and may lead to inadequate treatment. Having a functional biomarker will add to the clinical fidelity, diagnosis, and perhaps improve treatment efficacy in patients. While many approaches have been deployed in pain biomarker discovery, functional near-infrared spectroscopy (fNIRS) is a technology that allows for non-invasive measurement of cortical hemodynamics. The utility of fNIRS is especially attractive given its ability to detect specific changes in the somatosensory and high-order cortices as well as its ability to measure (1) brain function similar to functional magnetic resonance imaging, (2) graded responses to noxious and innocuous stimuli, (3) analgesia, and (4) nociception under anesthesia. In this review, we evaluate the utility of fNIRS in nociception/pain with particular focus on its sensitivity and specificity, methodological advantages and limitations, and the current and potential applications in various pain conditions. Everything considered, fNIRS technology could enhance our ability to evaluate evoked and persistent pain across different age groups and clinical populations.