Multiple models for outbreak decision support in the face of uncertainty.

Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Cardiac Vagal Nerve Activity Increases During Exercise to Enhance Coronary Blood Flow.

BACKGROUND: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine. METHODS: Chronic direct recordings of cardiac vagal nerve activity, cardiac output, coronary artery blood flow, and heart rate were recorded in conscious adult sheep during whole-body treadmill exercise. Cardiac innervation of the left cardiac vagal branch was confirmed with lipophilic tracer dyes (DiO). Sheep were exercised with pharmacological blockers of acetylcholine (atropine, 250 mg), VIP (vasoactive intestinal peptide; [4Cl-D-Phe6,Leu17]VIP 25 µg), or saline control, randomized on different days. In a subset of sheep, the left cardiac vagal branch was denervated. RESULTS: Neural innervation from the cardiac vagal branch is seen at major cardiac ganglionic plexi, and within the fat pads associated with the coronary arteries. Directly recorded cardiac vagal nerve activity increased during exercise. Left cardiac vagal branch denervation attenuated the maximum changes in coronary artery blood flow (maximum exercise, control: 63.5±5.9 mL/min, n=8; cardiac vagal denervated: 32.7±5.6 mL/min, n=6, P=2.5×10-7), cardiac output, and heart rate during exercise. Atropine did not affect any cardiac parameters during exercise, but VIP antagonism significantly reduced coronary artery blood flow during exercise to a similar level to vagal denervation. CONCLUSIONS: Our study demonstrates that cardiac vagal nerve activity actually increases and is crucial for maintaining cardiac function during exercise. Furthermore, our findings show the dynamic modulation of coronary artery blood flow during exercise is mediated by VIP.

Sympathetic transduction of cardiac sympathetic nerve activity in healthy, conscious sheep.

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a ß-adrenoceptor blocker (propranolol) to determine the role of ß-adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n = 10, ∆: +2.1 ± 1.4 beats min-1 , P = 0.002) and CO (n = 8, ∆: +100 ± 150 mL min-1 , P = 0.002) was elevated, followed by an increase in CoBF (n = 9, ∆: +0.76 mL min-1 , P = 0.001) and CVC (n = 8, ∆: +0.0038 mL min-1  mmHg-1 , P = 0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on ß-adrenoceptors. KEY POINTS: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by ß-adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by ß-adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

Progression and flaring of focal dermal hypoplasia during an acute illness.

Focal dermal hypoplasia (FDH), or Goltz syndrome, is a rare genodermatosis affecting tissues of mesodermal and ectodermal origin. The characteristic skin changes have been reported to symptomatically flare in response to certain triggers as well as to progress over time in some cases. We present the case of a 5-year-old girl with cutaneous flaring and progression of FDH in the setting of septic shock. This case adds to the growing body of literature on both flaring and progression of the cutaneous manifestations of FDH.

Increasing aggressive prostate cancer.

INTRODUCTION: To compare prostate biopsy (Pbx) characteristics, before and after the 2012 United States Preventive Services Task Force (USPSTF) prostate cancer screening guidelines in our practice. MATERIALS AND METHODS: We completed a retrospective comparative analysis of 1703 sequential patients that had a Pbx in 2010 to 2012 (3 years) with 1006 patients biopsied in 2018, 2019 and 2021 (3 years). Data from a total of 2709 Pbx was collected on patient age, race, prostate-specific antigen (PSA), digital rectal examination (DRE) and Gleason sum score (GSS). The data was analyzed to determine whether the 2012 USPSTF screening recommendations against prostate cancer screening may have affected prostate cancer characteristics. Two study groups were defined as Group A and Group B. Group A represents Pbx prior to the 2012 USPSTF screening guidelines (2010-2012) and Group B represents Pbx in 2018-19 and 2021. The patient population consisted of 76% Black, 14% White and 11% other. RESULTS: The number of patients that had a Pbx in Groups A vs. B: 567 patients/year vs. 335 patients/year. The annual positive Pbx rate for Group A vs. B: 134/year vs. 175/year. High grade prostate cancer (GSS 7-10) in Groups A vs. B: 51.5% vs. 59%. The proportion of patients with a PSA 10 ng/mL or greater in Groups A vs. B: 25.4% vs. 31%. The PSA 10 ng/mL and over and GSS 7-10 was higher in Group B for all age groups. In 2021, GSS 7-10 was present in 64% of 70-80 year olds. In Group B, GSS 6 decreased by 7.5% while GSS 7-10 increased by 7.5% compared with Group A. CONCLUSIONS: Our data through the year 2021 shows that after the 2012 USPSTF recommendations against prostate cancer screening, Pbx decreased and prostate cancer diagnosis and high grade (GSS 7-10) prostate cancer increased. As our patient population consists of 76% Black patients and 33% of men age 70-80 years old, our results support annual prostate cancer screening for US men 50-80 years old and especially high-risk patients that include Black men, men with a family history of prostate cancer and healthy men age 70-80 years old. Annual DRE- and PSA- based prostate cancer screening will likely markedly decrease prostate cancer morbidity, mortality and the cost of prostate cancer management.

Optimizing Emergency Stroke Transport Strategies Using Physiological Models.

BACKGROUND AND PURPOSE: The criteria for choosing between drip and ship and mothership transport strategies in emergency stroke care is widely debated. Although existing data-driven probability models can inform transport decision-making at an epidemiological level, we propose a novel mathematical, physiologically derived framework that provides insight into how patient characteristics underlying infarct core growth influence these decisions. METHODS: We represent the physiology of time-dependent infarct core growth within an ischemic penumbra as an exponential function with consideration to rate-determining collateral blood flow. Monte Carlo methods generate distributions of infarct core volumes, which are translated to distributions of 90-day modified Rankin Scale scores. We apply the model to a stroke network that serves rural Bastrop County and urban Travis County by simulating transport strategies from thousands of potential patient pickup locations. In every pickup location, the simulation yields a distribution of outcomes corresponding to each transport strategy. A 2-sample Kolmogorov-Smirnov test and Student t test determine which transport strategy provides a significantly better probability of a good outcome for a given pickup location in each respective county (P<0.01). RESULTS: In Travis County, drip and ship provides significantly better probabilities of a good outcome in 24.0% of the pickup locations, while 59.8% favor mothership. In Bastrop County, 11.3% of the pickup locations favor drip and ship, while only 7.1% favor mothership. The remaining pickup locations in each county are not statistically significant in either direction. We also reveal how differing rates of infarct core growth, the application of bypass policies, and the use of large vessel occlusion field tests impact these results. CONCLUSIONS: Modeling stroke physiology enables the use of clinically relevant metrics for determining comparative significance between drip and ship and mothership in a given geography. This formalism can help understand and inform emergency medical service transport decision-making, as well as regional bypass policies.

A mathematical model for persistent post-CSD vasoconstriction.

Cortical spreading depression (CSD) is the propagation of a relatively slow wave in cortical brain tissue that is linked to a number of pathological conditions such as stroke and migraine. Most of the existing literature investigates the dynamics of short term phenomena such as the depolarization and repolarization of membrane potentials or large ion shifts. Here, we focus on the clinically-relevant hour-long state of neurovascular malfunction in the wake of CSDs. This dysfunctional state involves widespread vasoconstriction and a general disruption of neurovascular coupling. We demonstrate, using a mathematical model, that dissolution of calcium that has aggregated within the mitochondria of vascular smooth muscle cells can drive an hour-long disruption. We model the rate of calcium clearance as well as the dynamical implications on overall blood flow. Based on reaction stoichiometry, we quantify a possible impact of calcium phosphate dissolution on the maintenance of F0F1-ATP synthase activity.

Characterizing the performance of emergency medical transport time metrics in a residentially segregated community.

OBJECTIVE: To derive and characterize the performance of various metrics of emergency transport time in assessing for sociodemographic disparities in the setting of residential segregation. Secondarily to characterize racial disparities in emergency transport time of suspected stroke patients in Austin, Texas. DATA SOURCES: We used a novel dataset of 2518 unique entries with detailed spatial and temporal information on all suspected stroke transports conducted by a public emergency medical service in Central Texas between 2010 and 2018. STUDY DESIGN: We conducted one-way ANOVA tests with post-hoc pairwise t-tests to assess how mean hospital transport times varied by patient race. We also developed a spatially-independent metric of emergency transport urgency, the ratio of expected duration of self-transport to a hospital and the measured transport time by an ambulance. DATA COLLECTION/EXTRACTION: We calculated ambulance arrival and destination times using sequential temporospatial coordinates. We excluded any entries in which patient race was not recorded. We also excluded entries in which ambulances' routes did not pass within 100 m of either the patient's location or the documented hospital destination. PRINCIPAL FINDINGS: We found that mean transport time to a hospital was 2.5 min shorter for black patients compared to white patients. However, white patients' transport times to a hospital were found to be, on average, 4.1 min shorter than expected compared to 3.4 min shorter than expected for black patients. One-way ANOVA testing for the spatially-independent index of emergency transport urgency was not statistically significant, indicating that average transport time did not vary significantly across racial groups when accounting for variations in transport distance. CONCLUSIONS: Using a novel transport urgency index, we demonstrate that these findings represent race-based variation in spatial distributions rather than racial bias in emergency medical transport. These results highlight the importance of closely examining spatial distributions when utilizing temporospatial data to investigate geographically-dependent research questions.

Falling off a limit cycle using phase-agnostic stimuli: Applications to clinical oscillopathies.

For over a century, physiological studies have shown that precisely timed pulses can switch off a biological oscillator. This empiric finding has shaped our mechanistic understanding of how perturbations start, stop, and reset biological oscillators and has led to treatments that suppress pathological oscillations using electrical pulses given within specified therapeutic phase windows. Here, we present evidence, using numerical simulations of models of epileptic seizures and reentrant tachycardia, that the phase window can be opened to the entire cycle using novel complex stimulus waveforms. Our results reveal that the trajectories are displaced by such phase-agnostic stimuli off the oscillator's limit cycle and corralled into a region where oscillation is suppressed, irrespective of the phase at which the stimulus was applied. Our findings suggest the need for broadening theoretical understanding of how complex perturbing waveforms interact with biological oscillators to access their arrhythmic states. In clinical practice, oscillopathies may be treated more effectively with non-traditional stimulus waveforms that obviate the need for phase specificity.

Falling off a limit cycle using phase-agnostic stimuli: Definitions and conceptual framework.

Nearly a half-century of biomedical research has revealed methods and mechanisms by which an oscillator with bistable limit cycle kinetics can be stopped using critical stimuli applied at a specific phase. Is it possible to construct a stimulus that stops oscillation regardless of the phase at which the stimulus is applied? Using a radial isochron clock model, we demonstrate the existence of such stimulus waveforms, which can take on highly complex shapes but with a surprisingly simple mechanism of rhythm suppression. The perturbation, initiated at any phase of the limit cycle, first corrals the oscillator to a narrow range of new phases, then drives the oscillator to its phase singularity. We further constructed a library of waveforms having different durations, each achieving phase-agnostic suppression of rhythm but with varying rates of phase corralling prior to amplitude suppression. The optimal stimulus energy to achieve phase-agnostic suppression of rhythm is dependent on the rate of phase corralling and the configuration of the phaseless set. We speculate that these results are generic and suggest the existence of stimulus waveforms that can stop the rhythm of more complex oscillators irrespective of the applied phase.

A Comparison of Cryoablation with Heat-Based Thermal Ablation for Treatment of Clinical T1a Renal Cell Carcinoma: A National Cancer Database Study.

PURPOSE: To compare the overall survival (OS) of patients receiving cryoablation versus heat-based thermal ablation for clinical T1a renal cell carcinoma (RCC) in a large national cohort. MATERIALS AND METHODS: Patients with RCC from 2004 to 2014 who were treated with ablation were identified from the National Cancer Database. OS was estimated with the use of the Kaplan-Meier method and evaluated by means of log-rank test, univariate and multivariate Cox proportional hazard regression, and propensity score-matched analysis. RESULTS: A total of 3,936 patients who received cryoablation and 2,322 who received heat-based thermal ablation met the inclusion criteria. The mean age was 67 ± 12 year, and the mean size of tumors was 25 ± 8 mm. The 3-, 5-, and 10-year survival rates were, respectively, 91%, 82%, and 62% for cryoablation and 89%, 81%, and 55% for heat-based thermal ablation. After propensity score matching, cryoablation was associated with longer OS compared with heat-based thermal ablation (median 11.3 vs 10.4 years; hazard ratio 1.175, 95% CI 1.03-1.341; P = .016). For patients with tumors ≤2 cm, propensity score-matched analyses demonstrated no significant difference between the 2 treatment groups (P = .772). CONCLUSIONS: Overall, cryoablation may be associated with longer OS compared with heat-based thermal ablation in cT1a RCC. No significant difference in survival rates was observed between the 2 treatments for patients with tumor sizes ≤2 cm. Owing to the inherent limitations of this study, further study with details on technology, local outcome, and complications is needed.

Optimizing stimulus waveforms for electroceuticals.

There has been a growing interest in the use of electrical stimulation as a therapy across diverse medical conditions. Most electroceutical devices use simple waveforms, for example sinusoidal or rectangular biphasic pulses. Clinicians empirically tune the waveform parameters (e.g. amplitude, frequency) without altering the fundamental shape of the stimulus. In this article, we review computational strategies that have been used to optimize the shape of stimulus waveforms in order to improve clinical outcomes, and we discuss potential directions for future exploration.

Reconstruction of Cell Focal Adhesions using Physical Constraints and Compressive Regularization.

We develop a method to reconstruct, from measured displacements of an underlying elastic substrate, the spatially dependent forces that cells or tissues impart on it. Given newly available high-resolution images of substrate displacements, it is desirable to be able to reconstruct small-scale, compactly supported focal adhesions that are often localized and exist only within the footprint of a cell. In addition to the standard quadratic data mismatch terms that define least-squares fitting, we motivate a regularization term in the objective function that penalizes vectorial invariants of the reconstructed surface stress while preserving boundaries. We solve this inverse problem by providing a numerical method for setting up a discretized inverse problem that is solvable by standard convex optimization techniques. By minimizing the objective function subject to a number of important physically motivated constraints, we are able to efficiently reconstruct stress fields with localized structure from simulated and experimental substrate displacements. Our method incorporates the exact solution for a stress tensor accurate to first-order finite differences and motivates the use of distance-based cutoffs for data inclusion and problem sparsification.

A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord.

The proper balance of excitatory and inhibitory neurons is crucial for normal processing of somatosensory information in the dorsal spinal cord. Two neural basic helix-loop-helix transcription factors (TFs), Ascl1 and Ptf1a, have contrasting functions in specifying these neurons. To understand how Ascl1 and Ptf1a function in this process, we identified their direct transcriptional targets genome-wide in the embryonic mouse neural tube using ChIP-Seq and RNA-Seq. We show that Ascl1 and Ptf1a directly regulate distinct homeodomain TFs that specify excitatory or inhibitory neuronal fates. In addition, Ascl1 directly regulates genes with roles in several steps of the neurogenic program, including Notch signaling, neuronal differentiation, axon guidance and synapse formation. By contrast, Ptf1a directly regulates genes encoding components of the neurotransmitter machinery in inhibitory neurons, and other later aspects of neural development distinct from those regulated by Ascl1. Moreover, Ptf1a represses the excitatory neuronal fate by directly repressing several targets of Ascl1. Ascl1 and Ptf1a bind sequences primarily enriched for a specific E-Box motif (CAGCTG) and for secondary motifs used by Sox, Rfx, Pou and homeodomain factors. Ptf1a also binds sequences uniquely enriched in the CAGATG E-box and in the binding motif for its co-factor Rbpj, providing two factors that influence the specificity of Ptf1a binding. The direct transcriptional targets identified for Ascl1 and Ptf1a provide a molecular understanding of how these DNA-binding proteins function in neuronal development, particularly as key regulators of homeodomain TFs required for neuronal subtype specification.

Regulatory inhibition of biological tissue mineralization by calcium phosphate through post-nucleation shielding by fetuin-A.

In vertebrates, insufficient availability of calcium and inorganic phosphate ions in extracellular fluids leads to loss of bone density and neuronal hyper-excitability. To counteract this problem, calcium ions are usually present at high concentrations throughout bodily fluids-at concentrations exceeding the saturation point. This condition leads to the opposite situation where unwanted mineral sedimentation may occur. Remarkably, ectopic or out-of-place sedimentation into soft tissues is rare, in spite of the thermodynamic driving factors. This fortunate fact is due to the presence of auto-regulatory proteins that are found in abundance in bodily fluids. Yet, many important inflammatory disorders such as atherosclerosis and osteoarthritis are associated with this undesired calcification. Hence, it is important to gain an understanding of the regulatory process and the conditions under which it can go awry. In this manuscript, we extend mean-field continuum classical nucleationtheory of the growth of clusters to encompass surface shielding. We use this formulation to study the regulation of sedimentation of calcium phosphate salts in biological tissues through the mechanism of post-nuclear shielding of nascent mineral particles by binding proteins. We develop a mathematical description of this phenomenon using a countable system of hyperbolic partial differential equations. A critical concentration of regulatory protein is identified as a function of the physical parameters that describe the system.

Sclerotic bone lesions at abdominal magnetic resonance imaging in children with tuberous sclerosis complex.

BACKGROUND: Sclerotic bone lesions are often seen on chest CT in adults with tuberous sclerosis complex. OBJECTIVE: To characterize bone lesions at abdominal MRI in children with tuberous sclerosis complex. MATERIALS AND METHODS: This retrospective review included 70 children with tuberous sclerosis complex who had undergone abdominal MRI for renal imaging. An additional longitudinal study was performed in 50 children who had had two or more MRI scans. Abdominal CT (eight children) and radiographs (three children) were reviewed and compared with MRI. RESULTS: A total of 173 sclerotic bone lesions were detected in 51/70 children (73%; 95% confidence interval: 0.61-0.82) chiefly affecting vertebral pedicles. New lesions appeared in 20 children and growth of previous sclerotic bone lesions was documented in 14 children. Sclerotic bone lesions were more frequent in girls and in children with more extensive renal involvement. CONCLUSION: Sclerotic bone lesions are commonly detected by abdominal MRI in children with tuberous sclerosis complex. They usually affect posterior vertebral elements and their number and size increase with age. As current recommendations for tuberous sclerosis complex surveillance include renal MR performed in childhood, recognition of these lesions is useful.

Mutant SOD1 protein increases Nav1.3 channel excitability.

Amyotrophic lateral sclerosis (ALS) is a lethal paralytic disease caused by the degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) are present in ~20% of familial ALS and ~2% of all ALS cases. The most common SOD1 gene mutation in North America is a missense mutation substituting valine for alanine (A4V). In this study, we analyze sodium channel currents in oocytes expressing either wild-type or mutant (A4V) SOD1 protein. We demonstrate that the A4V mutation confers a propensity to hyperexcitability on a voltage-dependent sodium channel (Nav1.3) mediated by heightened total Na(+) conductance and a hyperpolarizing shift in the voltage dependence of Nav1.3 activation. To estimate the impact of these channel effects on excitability in an intact neuron, we simulated these changes in the program NEURON; this shows that the changes induced by mutant SOD1 increase the spontaneous firing frequency of the simulated neuron. These findings are consistent with the view that excessive excitability of neurons is one component in the pathogenesis of this disease.

Bayesian Uncertainty Quantification for Bond Energies and Mobilities Using Path Integral Analysis.

Dynamic single-molecule force spectroscopy is often used to distort bonds. The resulting responses, in the form of rupture forces, work applied, and trajectories of displacements, are used to reconstruct bond potentials. Such approaches often rely on simple parameterizations of one-dimensional bond potentials, assumptions on equilibrium starting states, and/or large amounts of trajectory data. Parametric approaches typically fail at inferring complicated bond potentials with multiple minima, while piecewise estimation may not guarantee smooth results with the appropriate behavior at large distances. Existing techniques, particularly those based on work theorems, also do not address spatial variations in the diffusivity that may arise from spatially inhomogeneous coupling to other degrees of freedom in the macromolecule. To address these challenges, we develop a comprehensive empirical Bayesian approach that incorporates data and regularization terms directly into a path integral. All experimental and statistical parameters in our method are estimated directly from the data. Upon testing our method on simulated data, our regularized approach requires less data and allows simultaneous inference of both complex bond potentials and diffusivity profiles. Crucially, we show that the accuracy of the reconstructed bond potential is sensitive to the spatially varying diffusivity and accurate reconstruction can be expected only when both are simultaneously inferred. Moreover, after providing a means for self-consistently choosing regularization parameters from data, we derive posterior probability distributions, allowing for uncertainty quantification.