The reconstruction of electrical excitation patterns through the unobserved depth of the tissue is essential to realizing the potential of computational models in cardiac medicine. We have utilized experimental optical-mapping recordings of cardiac electrical excitation on the epicardial and endocardial surfaces of a canine ventricle as observations directing a local ensemble transform Kalman Filter (LETKF) data assimilation scheme. We demonstrate that the inclusion of explicit information about the stimulation protocol can marginally improve the confidence of the ensemble reconstruction and the reliability of the assimilation over time. Likewise, we consider the efficacy of stochastic modeling additions to the assimilation scheme in the context of experimentally derived observation sets. Approximation error is addressed at both the observation and modeling stages, through the uncertainty of observations and the specification of the model used in the assimilation ensemble. We find that perturbative modifications to the observations have marginal to deleterious effects on the accuracy and robustness of the state reconstruction. Further, we find that incorporating additional information from the observations into the model itself (in the case of stimulus and stochastic currents) has a marginal improvement on the reconstruction accuracy over a fully autonomous model, while complicating the model itself and thus introducing potential for new types of model error. That the inclusion of explicit modeling information has negligible to negative effects on the reconstruction implies the need for new avenues for optimization of data assimilation schemes applied to cardiac electrical excitation.

Before the Perseverance rover landing, the acoustic environment of Mars was unknown. Models predicted that: (1) atmospheric turbulence changes at centimetre scales or smaller at the point where molecular viscosity converts kinetic energy into heat 1 , (2) the speed of sound varies at the surface with frequency 2 , 3 and (3) high-frequency waves are strongly attenuated with distance in CO 2 (refs. 2 – 4 ). However, theoretical models were uncertain because of a lack of experimental data at low pressure and the difficulty to characterize turbulence or attenuation in a closed environment. Here, using Perseverance microphone recordings, we present the first characterization of the acoustic environment on Mars and pressure fluctuations in the audible range and beyond, from 20 Hz to 50 kHz. We find that atmospheric sounds extend measurements of pressure variations down to 1,000 times smaller scales than ever observed before, showing a dissipative regime extending over five orders of magnitude in energy. Using point sources of sound (Ingenuity rotorcraft, laser-induced sparks), we highlight two distinct values for the speed of sound that are about 10 m s −1 apart below and above 240 Hz, a unique characteristic of low-pressure CO 2 -dominated atmosphere. We also provide the acoustic attenuation with distance above 2 kHz, allowing us to explain the large contribution of the CO 2 vibrational relaxation in the audible range. These results establish a ground truth for the modelling of acoustic processes, which is critical for studies in atmospheres such as those of Mars and Venus.

Reconstructions of excitation patterns in cardiac tissue must contend with uncertainties due to model error, observation error, and hidden state variables. The accuracy of these state reconstructions may be improved by efforts to account for each of these sources of uncertainty, in particular, through the incorporation of uncertainty in model specification and model dynamics. To this end, we introduce stochastic modeling methods in the context of ensemble-based data assimilation and state reconstruction for cardiac dynamics in one- and three-dimensional cardiac systems. We propose two classes of methods, one following the canonical stochastic differential equation formalism, and another perturbing the ensemble evolution in the parameter space of the model, which are further characterized according to the details of the models used in the ensemble. The stochastic methods are applied to a simple model of cardiac dynamics with fast-slow time-scale separation, which permits tuning the form of effective stochastic assimilation schemes based on a similar separation of dynamical time scales. We find that the selection of slow or fast time scales in the formulation of stochastic forcing terms can be understood analogously to existing ensemble inflation techniques for accounting for finite-size effects in ensemble Kalman filter methods; however, like existing inflation methods, care must be taken in choosing relevant parameters to avoid over-driving the data assimilation process. In particular, we find that a combination of stochastic processes-analogously to the combination of additive and multiplicative inflation methods-yields improvements to the assimilation error and ensemble spread over these classical methods.

It is demonstrated that the unusual failure of unidirectional hybrid carbon and glass fiber composite rods under bending and tension can be explained by a combined experimental, analytical, and numerical analysis. To simulate possible transportation, in-service, and installation conditions, ACCC® conductor cores, manufactured by CTC Global,were tested in three- and four-point bending experiments. Axial stresses were predicted analytically and numerically with the likely failure initiating locations identified for rods subjected to bending with applied axial tension. As expected under pure bending, composite rods will fail catastrophically from excessive compressive stress in the carbon composite region. The initiating damage mechanisms will change from compressive to tensile modes as axial tension increases. Natural fiber misalignment must be considered in the failure analysis of composite rods as it can significantly reduce bending strength and influence the locations of damage initiation.

OBJECTIVE:To determine the diagnostic sensitivity and specificity and comparative effectiveness of traditional sleep apnea screening tools in traumatic brain injury (TBI) neurorehabilitation admissions.DESIGN:Prospective diagnostic comparative effectiveness trial of sleep apnea screening tools relative to the criterion standard, attended level 1 polysomnography including encephalography.SETTING:Six TBI Model System Inpatient Rehabilitation Centers.PARTICIPANTS:Between May 2017 and February 2019, 449 of 896 screened were eligible for the trial with 345 consented (77% consented). Additional screening left 263 eligible for and completing polysomnography with final analyses completed on 248.INTERVENTION:Not applicable.MAIN OUTCOME MEASURES:Area under the curve (AUC) of screening tools relative to total apnea hypopnea index≥15 (AHI, moderate to severe apnea) measured at a median of 47 days post-TBI (interquartile range, 29-47).RESULTS:The Berlin high-risk score (receiving operating curve [ROC] AUC=0.634) was inferior to the Multivariable Apnea Prediction Index (MAPI) (ROC AUC=0.780) (P=.0211; CI, 0.018-0.223) and Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender (STOPBANG) score (ROC AUC=0.785) (P=.001; CI, 0.063-0.230), both of which had comparable AUC (P=.7245; CI, -0.047 to 0.068). Findings were similar for AHI≥30 (severe apnea); however, no differences across scales was observed at AHI≥5. The pattern was similar across TBI severity subgroups except for posttraumatic amnesia (PTA) status wherein the MAPI outperformed the Berlin. Youden's index to determine risk yielded lower sensitivities but higher specificities relative to non-TBI samples.CONCLUSION:This study is the first to provide clinicians with data to support a choice for which sleep apnea screening tools are more effective during inpatient rehabilitation for TBI (STOPBANG, MAPI vs Berlin) to help reduce comorbidity and possibly improve neurologic outcome.

Abstract Background: PAL , an oral cyclin dependent kinase (CDK) 4/6 inhibitor, is under investigation in multiple oncologic clinical trials and is currently approved for use in multiple countries in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC). International Conference on Harmonization guidance recommends that all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most non-adjuvant anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in patients [pts] is required in the registration dossier. The phase 3 PALOMA-2 study (N=666) confirmed the superior clinical benefit of PAL+LET vs placebo (P) + LET in postmenopausal women with estrogen receptor positive/HER2– ABC who have not received any prior systemic anticancer therapies for ABC. One of the secondary objectives of the study was to evaluate the effects of PAL+LET on QTc. Methods: 12 lead (with a 10 second rhythm strip) tracings were performed in triplicate ∼2 min apart but within 10 min for all 3 ECGs. On the day preceding the initiation of treatment (Day 0), triplicate ECGs were obtained at time 0, 2, 4, 6, and 8 hrs (baseline). On Cycle 1 Day 14, when PAL concentrations were at steady-state, triplicate ECGs time-matched to baseline ECGs collected on Day 0 (±35 min) were obtained following PAL or P dosing. All ECGs were sent to a central laboratory for blinded manual adjudication and these data were used for analysis. ECG measurements included PR interval, QT interval, RR interval and QRS complex. The QT interval was corrected for the effect of heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). Approximately 60 pts were to be included for QTc evaluation to ensure 40 evaluable pts in the PAL+LET arm (2:1 randomization) of PALOMA-2 and thus, to establish noninferiority between post-baseline and baseline (ΔQTc) at all 5 QTc sampling timepoints on Cycle 1 Day 14 with 90% power. The test was based on a 1-sided difference in means t test for paired ΔQTc (α= 0.05). The difference in means between ΔQTc under the alternative hypothesis is 10 ms, assuming a noninferiority margin of 20 ms and the standard deviation of the paired differences equal to 16 ms based on PALOMA-1 study. If the upper bounds (UB) of 1-sided 95% confidence intervals (CI) of ΔQTc for all 5 QTc time points were <20 ms, the post-baseline QTc will be considered noninferior to baseline and PAL+LET effect on QTc will be concluded to be not of clinical relevance. Results: A total of 77 pts were enrolled for intensive QTc assessment in PAL+LET arm. No pts had a post-baseline absolute maximum QTcF, QTcS or QTcB ≥500 ms or a ΔQTc ≥60 ms during the intensive QTc assessment period. A random effect analysis of the mean ΔQTc data demonstrated that the UB of the 1-sided 95% CI for QTcF, QTcS, and QTcB were <8 ms at all 5 QTc sampling time points. Conclusion: PAL+LET does not have a clinically relevant effect on QTc. Sponsor: Pfizer Citation Format: Ruiz A, Gauthier E, Durairaj C, Huang X, Hoffman J, Finn RS, Moulder S, Joy AA, Ettl J, Rugo HS, Wang D. Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-10.

Background: PAL , an oral cyclin dependent kinase (CDK) 4/6 inhibitor, is under investigation in multiple oncologic clinical trials and is currently approved for use in multiple countries in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC). International Conference on Harmonization guidance recommends that all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most non-adjuvant anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in patients [pts] is required in the registration dossier. The phase 3 PALOMA-2 study (N=666) confirmed the superior clinical benefit of PAL+LET vs placebo (P) + LET in postmenopausal women with estrogen receptor positive/HER2– ABC who have not received any prior systemic anticancer therapies for ABC. One of the secondary objectives of the study was to evaluate the effects of PAL+LET on QTc. Methods: 12 lead (with a 10 second rhythm strip) tracings were performed in triplicate ∼2 min apart but within 10 min for all 3 ECGs. On the day preceding the initiation of treatment (Day 0), triplicate ECGs were obtained at time 0, 2, 4, 6, and 8 hrs (baseline). On Cycle 1 Day 14, when PAL concentrations were at steady-state, triplicate ECGs time-matched to baseline ECGs collected on Day 0 (±35 min) were obtained following PAL or P dosing. All ECGs were sent to a central laboratory for blinded manual adjudication and these data were used for analysis. ECG measurements included PR interval, QT interval, RR interval and QRS complex. The QT interval was corrected for the effect of heart rate using Fridericia9s correction (QTcF), Bazett9s correction (QTcB), and a study-specific correction factor (QTcS). Approximately 60 pts were to be included for QTc evaluation to ensure 40 evaluable pts in the PAL+LET arm (2:1 randomization) of PALOMA-2 and thus, to establish noninferiority between post-baseline and baseline (ΔQTc) at all 5 QTc sampling timepoints on Cycle 1 Day 14 with 90% power. The test was based on a 1-sided difference in means t test for paired ΔQTc (α= 0.05). The difference in means between ΔQTc under the alternative hypothesis is 10 ms, assuming a noninferiority margin of 20 ms and the standard deviation of the paired differences equal to 16 ms based on PALOMA-1 study. If the upper bounds (UB) of 1-sided 95% confidence intervals (CI) of ΔQTc for all 5 QTc time points were Results: A total of 77 pts were enrolled for intensive QTc assessment in PAL+LET arm. No pts had a post-baseline absolute maximum QTcF, QTcS or QTcB ≥500 ms or a ΔQTc ≥60 ms during the intensive QTc assessment period. A random effect analysis of the mean ΔQTc data demonstrated that the UB of the 1-sided 95% CI for QTcF, QTcS, and QTcB were Conclusion: PAL+LET does not have a clinically relevant effect on QTc. Sponsor: Pfizer Citation Format: Ruiz A, Gauthier E, Durairaj C, Huang X, Hoffman J, Finn RS, Moulder S, Joy AA, Ettl J, Rugo HS, Wang D. Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-10.

Reentrant electrical scroll waves have been shown to underlie many cardiac arrhythmias, but the inability to observe locations away from the heart surfaces and the restriction of observations to only one or two state variables have made understanding arrhythmia mechanisms challenging. Recently, we showed that data assimilation from spatiotemporally sparse surrogate observations could be used to reconstruct a reliable time series of state estimates of reentrant cardiac electrical waves including unobserved variables in one and three spatial dimensions. However, real cardiac tissue is unlikely to be described accurately by mathematical models because of errors in model formulation and parameterization as well as intrinsic but poorly described spatial heterogeneity of electrophysiological properties in the heart. Here, we extend our previous work to assess how model error affects the accuracy of cardiac state estimates achieved using data assimilation with the Local Ensemble Transform Kalman Filter. We focus on one-dimensional states of discordant alternans characterized by significant wavelength oscillations. We demonstrate that data assimilation can provide high-quality estimates under a wide range of model error conditions, ranging from varying one or more parameter values to using an entirely different model to generate the truth state. We illustrate how multiplicative and additive inflation can be used to reduce error in the state estimates. Even when the truth state contains underlying spatial heterogeneity, we show that using a homogeneous model in the data assimilation algorithm can achieve good results. Overall, we find data assimilation to be a robust approach for reconstructing complex cardiac electrical states corresponding to arrhythmias even in the presence of model error.

For many years, reentrant scroll waves have been predicted and studied as an underlying mechanism for cardiac arrhythmias using numerical techniques, and high-resolution mapping studies using fluorescence recordings from the surfaces of cardiac tissue preparations have confirmed the presence of visible spiral waves. However, assessing the three-dimensional dynamics of these reentrant waves using experimental techniques has been limited to verifying stable scroll-wave dynamics in relatively thin preparations. We propose a different approach to recovering the three-dimensional dynamics of reentrant waves in the heart. By applying techniques commonly used in weather forecasting, we combine dual-surface observations from a particular experiment with predictions from a numerical model to reconstruct the full three-dimensional time series of the experiment. Here, we use model-generated surrogate observations from a numerical experiment to evaluate the performance of the ensemble Kalman filter in reconstructing such time series for a discordant alternans state in one spatial dimension and for scroll waves in three dimensions. We show that our approach is able to recover time series of both observed and unobserved variables matching the truth. Where nearby observations are available, the error is reduced below the synthetic observation error, with a smaller reduction with increased distance from observations. Our findings demonstrate that state reconstruction for spatiotemporally complex cardiac electrical dynamics is possible and will lead naturally to applications using real experimental data.

Objective To examine headache and depression over time in individuals who sustained mild traumatic brain injury (mTBI). Prevalence of headache and depression early after mTBI and at 1 year postinjury as well as the relationship between the two are evaluated. Background Headache is the most common physical symptom and depression is among the most common psychiatric diagnosis after traumatic brain injury regardless of severity. Headache and depression have been found to be two independent factors related to poor outcome after mTBI, yet there appears to be a paucity of research exploring the comorbidity of these two conditions after injury. Method/Design Longitudinal survey design over 1 year of 212 participants with mTBI who were admitted to a Level 1 trauma center for observation or other system injuries. Depression was based on a score ≥10 on the Patient Health Questionnaire‐9. Headache was based on participant report of new or worse‐than‐preinjury headache since hospitalization (baseline) or within the previous 3 months at 1 year postinjury. Results The prevalence of headache and depression at baseline was 64% (135/212) and 15% (31/212), respectively. The prevalence of headache and depression at 1 year was 68% (127/187) and 27% (50/187), respectively. The co‐occurrence of headache and depression increased from 11% (23/212) at baseline to 25% (46/187) at 1 year. At 1 year, the risk ratio of individuals who had headache to be depressed was 5.43 (95% CI 2.05–14.40) compared to those without headache ( P < .001). The corresponding risk ratio at baseline was 1.64 (95% CI .77–3.49; P = .23). Conclusions While prevalence of headache is consistently high over the first year after injury, rate of depression increased over the first year for those who were followed. Given the high rate of comorbidity, those with headache may develop depression over time. Evaluation for possible depression in those with headache after mTBI should be conducted to address both conditions over the year following injury.

Headache (HA) is the most frequently reported symptom following TBI. However, little is known about the natural history of posttraumatic headache (PTH) or its impact over time. We describe the natural history of posttraumatic headache (PTH) in individuals following moderate to severe traumatic brain injury up to five years after injury.

ur te sy o f TM f or W om en Drawing from 23 years of personal experience as well as input from other nurse entrepreneurs, Vicki D. Lachman (1998) writes, “Caring for the self as an entrepreneur requires courage, commitment, and persistence in self-care activities. . . . Walk a mile, meditate, eat fresh fruits, get a mammogram, assert yourself – all these behaviors require the initiative of an individual interested in taking responsibility for his or her health” (p. 48).