T1-mapping using the Shortened Modified Look-Locker Inversion Recovery (ShMOLLI) technique enables non-invasive assessment of important myocardial tissue characteristics. However, tachyarrhythmia may cause mistriggering and inaccurate T1 estimation. We set out to test whether systolic T1-mapping might overcome this, and whether T1 values or data quality would be significantly different compared to conventional diastolic T1-mapping.n = 13 atrial fibrillation, n = 2 sinus tachycardia; mean HR range 93–121 bpm).Native T1 maps were acquired using ShMOLLI at 1.5 T  in 10 healthy volunteers  in sinus rhythm, at varying prescribed trigger delay (TD) times: 0, 50, 100 and 150 ms , 340 ms  and also “end diastolic”. T1 maps were also acquired using a shorter readout, to explore the effect of reducing image readout time and sensitivity to systolic motion. The feasibility and image quality of systolic T1-mapping was tested in 15 patients with tachyarrhythmia (p = 0.04), with slightly shorter T1 values in systole compared to diastole (maximum difference 10 ms). While there were apparent gender differences , dilatation and erosion of contours suggested that the effect of TD on T1 in females was almost entirely due to more partial-volume effects in diastole. All T1 maps were of excellent quality, but systolic TD and shorter readout were associated with less variability in segmental T1 values. In tachycardic patients, systolic acquisitions produced consistently excellent T1 maps (median R2 = 0.993).In healthy volunteers, systolic readout increased the thickness of myocardium compared to the diastolic readout. There was a small overall effect of TD on T1 values  and aids the investigation of thinner myocardial segments. With further validation, systolic T1-mapping may become a new and convenient standard for myocardial T1-mapping. Myocardial T1-mapping is a quantitative technique that permits non-invasive assessment of biologically important properties of regional and global myocardium, independent of cardiac function –7. VarioThe recently described Shortened Modified Look-Locker Inversion Recovery (ShMOLLI) method uses sequential inversion recovery measurements, permitting a T1 map to be acquired within a short 9-heartbeat single breath-hold , which hThe ShMOLLI sequence uses a fixed post-R-wave trigger delay of 340 ms and the resultant trigger time of ~600 ms equates to readout in mid-diastole for typical heart rates (e.g. 60–80 bpm). However, many cardiac diseases are associated with tachyarrhythmia , which can lead to mistriggering and inaccurate T1 estimations. Consequently, the application of inversion recovery T1-mapping methods in cardiac patients with tachyarrhythmias is severely limited.Our attempts to address this problem during daily clinical imaging led to the hypothesis that reduction in ShMOLLI trigger delay (i.e. “systolic” T1 mapping) may circumvent this issue without significantly affecting estimated T1 values or data quality compared to a conventional diastolic readout. In this study, we systematically altered the ShMOLLI sequence parameters to investigate the effects of systolic T1-mapping on T1 values and data quality in healthy volunteers. We also report initial experience with systolic T1-mapping in patients with tachyarrhythmia.Ethical approval was granted for all study procedures and all subjects gave written informed consent.Ten healthy volunteers  in normal sinus rhythm (HR 61 ± 9 bpm), without symptoms or history of cardiac disease, not on cardiovascular medications and with normal left ventricular function on CMR were included.All data were collected on a 1.5 Tesla MR system  using a 32-channel cardiac coil array. T1 maps were acquired without administration of any contrast agents based on a prototype ShMOLLI implementation  .The goal was to alter the image sampling within the cardiac cycle using the permissible range of physiological trigger delay (TD), which, in this WIP implementation, is defined as the time from the R-wave to the start of the inversion preparation in the sequence. Figure short readout” . Conversely, the latest readout is limited by the subsequent R-wave. Based on earlier experience we decreased the automatic end-diastolic TD by 50 ms to reduce the occurrence of mistriggering. Full sequence parameters for all combinations tested are provided in the supplementary data.The duration of required preparations limits the shortest MOLLI TD to 270 ms. In order to achieve sampling earlier in the cardiac cycle, we reduced the MOLLI TI increment from 80 to 60 ms , which sA subset of two volunteers underwent a pre-study pilot scan to inform experimental design. Serial T1 maps were acquired with systematic alteration of physiological TD in 50 ms increments from 0 to 500 ms. Based on these data, four “systolic” TDs leading to imaging earlier in the cardiac cycle were chosen for further evaluation: 0, 50, 100 and 150 ms.Following standard planning, end-expiration basal, mid-ventricular and apical short-axis slice positions were selected and used for all T1 maps.Serial native (or pre-contrast) T1 maps were acquired in a semi-automated fashion using recorded breathing instructions. This minimised variability and ensured that at least 20 s passed between any two T1 maps, to allow sufficient time for full T1 relaxation between experiments.short readout parameters for matrix size and TI increment as described above and another with the normal readout. In five volunteers, the order of acquisition of the T1 maps was randomised to minimise systematic intra-scan effects (such as change in heart rate or compliance with breathing instructions).At each slice position, six different TDs were investigated: the four “systolic” TDs chosen from the pilot experiments , conventional ShMOLLI  and imaging in “end-diastole” (defined as the captured cycle TD minus 50 ms). For each of these six TDs, two separate T1 maps were acquired: one with the normal and short readout, a total of 36 T1 maps were provided from each volunteer. R2 maps (of goodness-of-fit for how well T1 model fitting was achieved for each T1 map) were visually assessed in real time during the scan; acquisitions were repeated if quality was deemed insufficient . Endo- and epicardial contours were manually traced on each T1 map, taking care to avoid partial-volume effects of neighbouring tissues. Each slice was then divided into six segments, using the anterior right-ventricular-left-ventricular insertion point as reference. All voxels in each myocardial segment were analysed, and segmental data extracted for further analysis included mean T1 value, standard deviation of T1 value and median R2 maps by an assessor blinded to TD and normal/short readout. Segments with suspected artefacts were rejected. Further assessment of quality of T1 maps was provided by analysis of the standard deviation of segmental T1 values; this is a surrogate for T1 map quality in healthy volunteers without known myocardial pathology .Quality assessment of T1 maps was performed as previously described . The preThe thickness of myocardium was the average distance between epi- and endocardial outlines towards the centre of the left ventricle. The impact of partial-volume was studied by inflating and eroding the myocardial outlines as previously described . We alson = 13 atrial fibrillation, n = 2 sinus tachycardia). The degree of tachycardia  meant that acquisition using the conventional ShMOLLI sequence parameters would result in mistriggering and it was therefore not possible to directly compare the systolic readout against the conventional sequence in this population without compromising T1 values.In order to examine the feasibility and image quality of systolic ShMOLLI T1-mapping, we tested systolic acquisitions (TD 0 ms–TD 150 ms) in 15 patients with tachyarrhythmia. All patients underwent CMR examinations at 1.5 Tesla  for clinical indications and had a mean HR range between 93 and 121 bpm , to demonstrate the occasional need to adjust the TD to optimise T1 fit and improve T1 estimation.Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 20.0  and GraphPad Prism version 6 . Normality of data was assessed using the Kolmogorov-Smirnov test. Most variables including T1 and T1 SD did not follow a strictly Gaussian distribution; hence, all statistical tests used were non-parametric. For consistency with other literature reports, we present T1 as mean ± SD; non-parametric data are presented as median and range/IQR.short versus normal readout (2 groups). P values < 0.05 (after adjustment for multiple comparisons) were considered significant (*) with smaller P values stratified by size .The Kruskal-Wallis test was used to assess the effect of TD (6 groups); pairwise comparisons were made using the Bonferroni-Dunn approach for variables where the Kruskal-Wallis test was significant. The Kolmogorov-Smirnov test was used to assess effect of normal/short readout, the respective maps yielded estimates of 180 myocardial segments (10 volunteers × 3 slices × 6 segments), making a total of 2160 segments collected in the experiment. 54 (2.5 %) segments were excluded due to the presence of suspected image artefacts, leaving 2106 (97.5 %) segments in the final analysis. The variants with short TD (0–50 ms) had the lowest rejection rates  and the end-diastolic readout the largest . Using the short readout resulted in a minor (0.7 %) improvement in segment rejection rates compared to the normal readout.For each of the 12 combinations of TD and 2 values of at least 0.996. Sample mid-ventricular T1 and R2 maps for two systolic TDs and TD 340 ms (standard ShMOLLI) with both short and normal readout are shown in Fig. 2 maps have an otherwise similar visual appearance irrespective of the combination of sequence parameters.All included T1 maps were of excellent quality, with median Rp < 0.001). The variation in trigger time (TT) led to acquisition of T1 maps at different points in the cardiac cycle, with resultant increased myocardial thickness in the systolic acquisitions compared to conventional ShMOLLI or the end-diastolic acquisition.Across all subjects, the maximal thickness on T1 maps was achieved at TT ~ 320 ms (prescribed TD = 50–100 ms) at 7.5 ± 2.5 mm compared to the standard or end-diastolic acquisitions at 4.7 ± 2 mm . This improvement was possibly due to increased voxel volume (~19 %) and thus higher SNR, and was independent of TD.TD had no effect on fit quality, as assessed by Rp = 0.04), none of the pairwise comparisons of TD reached statistical significance . Overall significance was lost with minimisation of the partial-volume effects by erosion of myocardial contours (see below). T1 values were not affected by normal/short readout . Short readout was associated with a lower standard deviation of segmental T1 values than normal readout .The TD and ues Fig. . TD < 15Partial-volume effects appear to underlie most of the significant dependencies of T1 values identified above, as revealed by inflation and deflation of the myocardial contours.p = ns for all). Conversely, the dependence became stronger with any degree of myocardial outline dilatation, and reached statistical significance (p ≤ 0.001) for 2 or 3 pixel dilatation when comparing TD 50 ms to conventional diastolic ShMOLLI (TD 340 ms)  became smaller with any degree of myocardial erosion or centreline T1 estimates, with no statistical significance (ms) Fig. .Fig. 4EfPartial-volume effects also appear to underlie most of the effect of TD on intra-segmental pixel T1 variability. Even when the difference is at its strongest comparing the T1 maps acquired with TD = 50 ms versus standard ShMOLLI , the statistical significance is amplified by myocardial contour dilatation but lost for any degree of erosion Fig. .A much stronger dependency of T1 values on TD was noted in females Fig.  than in p < 0.001). However in males, there was no significant effect of TD on T1 values, with a maximum difference of 5 ms .In females, diastolic T1 values were a maximum of 20 ms longer than systolic ones . In contrast, T1 values were significantly higher with the diastolic compared to the systolic readout in the thinner segments . We infer that the differences seen in T1 values between systolic and diastolic readout in females were driven by greater partial-volume effects in diastole , with thinner myocardium much more susceptible to this phenomenon.To ascertain if this was driven by partial-volume effects, we re-analysed the female data for myocardial segments with a thickness in the lowest and highest tertiles of thickness for the female participants . A summary of patient characteristics and T1 and R2 results is presented in Table In 15 patients with tachyarrhythmia (mean HR range 93–121 bpm), systolic ShMOLLI acquisition parameters produced consistently excellent T1 maps  resulted in mistriggering in such patients, leading to poor estimation of T1 values. A representative example of this effect is shown in Fig. In contrast, our initial attempts to acquire T1 maps using the conventional sequence parameters  yields T1 values that are clinically equivalent to those derived by the conventional sequence in healthy volunteers, with the benefit of a slight improvement in data quality. Furthermore, these data suggest that, in healthy volunteers, the T1 differences between diastolic and systolic readout are driven by reduced partial-volume effects in systole due to functionally increased myocardial thickness, implying that the systolic readout may provide a more robust sample of myocardial T1. Finally, we have established that this technique is feasible and produces consistently excellent T1 maps in patients with tachyarrhythmia. To the best of our knowledge, this is the first evaluation and application of a systolic readout inversion recovery method for T1 mapping in tachyarrhythmia, which is highly relevant for real-world clinical applications.et al. compared a single systolic trigger delay time of 150 ms (“early systole”) with conventional mid- to end-diastolic readout in healthy volunteers, and found diastolic T1 values higher than systolic values, with mean differences of 5 and 15 ms in native T1 values on separate examinations at 3 Tesla  [et al. reported an even larger mean difference of 25 ms (984 ms in diastole and 959 ms in systole) [Our findings of slightly lower T1 values in systole compared to diastole concur in general with some previous reports on the effects of systolic readout using other MOLLI-based sequences , 17. Kaweported) . Reiter The mechanism for these differences has been attributed to myocardial contraction, which is known to compress the myocardial vascular bed . Reducedet al. [et al. [et al. [However, our initial findings  have beeet al. , who com [et al.  and Reit [et al.  may emphet al. [et al. who studied a heterogeneous group of patients with a variety of myocardial pathologies, including previous myocardial infarction, cardiomyopathy, valve disease, and athletes with echocardiographic or ECG abnormalities. This patient population may have contributed to high rejection rates of myocardial segments in their study, either because they were pathologic on visual evaluation (~7 %) or because they were judged ineligible for analysis (~21 % for diastolic T1 maps) [2 and coloured T1 maps, we achieved a segmental exclusion rate as low as 2.5 %, offering clear diagnostic benefit when assessing pathological T1 changes.In line with the discussion of future research in Tessa et al. , we systT1 maps) . With thet al. [We have also extended the initial investigations of Tessa et al.  into theEnd systole has a shorter quiescent period than end diastole , but is 2 maps, with the correct timing determined to be TD 100 ms on cine images, and repeat acquisition with this TD resulted in an excellent quality T1 map  was chosen for simplicity in the majority of these patients, minimising TT and thus maximising heart rate tolerated before mistriggering occurs. The presented healthy volunteer data suggest that a choice of TD 50 ms (corresponding to a TT of 250–300 ms) might serve better to maximise the myocardial thickness. In practice, the only situation in which we have found the choice of TD 0 ms to be suboptimal was in atrial fibrillation with a slow ventricular response. In a patient with such a rhythm (mean HR 40–50 bpm), we noted cardiac motion artefact on raw images, indicating data acquisition during mid-systolic ventricular contraction (rather than the relative lack of cardiac motion characteristic of end-systole). The artefact was easy to identify on Rmap Fig. .Fig. 7Exthrough-plane motion. Subjects who have difficulty breath-holding  would likely benefit from a combination of both approaches, but this was not specifically tested in this study.The number of volunteers included in this study is relatively small, but effects of inter-individual differences are reduced as all combinations of sequence parameters were undertaken in all volunteers. While we tested a specific implementation of ShMOLLI with its corresponding conditional reconstruction, the primary hypothesis has been independently confirmed by another research group using the classic 17-heart-beat MOLLI variant . We focuThe main limitation for the current evidence in the field is that it is only observational - much further work is needed on simulating the underlying biophysical mechanisms. In particular, it would be hard to extrapolate the current findings to saturation-recovery based techniques, in which end-diastolic readout is usually preferred in order to enable robust saturation time sampling within a single heartbeat. These techniques also do not average T1 recovery over several heartbeats and thus may have different sensitivity to the myocardial blood volumes during the sequence evolution.In healthy volunteers, systolic ShMOLLI T1-mapping reduces T1 variability and reports clinically equivalent T1 values to conventional diastolic readout; slightly shorter T1 values in systole are mostly explained by reduced partial-volume effects due to the increase in functional myocardial thickness. In patients with tachyarrhythmia, systolic ShMOLLI T1-mapping is feasible, circumvents mistriggering and produces excellent quality T1-maps. This extends its clinical applicability to challenging rhythms  and aids the investigation of thinner myocardial segments. With further validation, systolic T1-mapping may become a new and convenient standard for myocardial T1-mapping.


Objectives. To better understand the etiology of HFpEF in a controlled human population, regional time-varying strains were computed using echocardiography speckle tracking in patients with heart failure with a preserved ejection fraction and normal subjects. Methods. Eleven normal volunteers and ten patients with echo-graded diastolic dysfunction and symptoms of heart failure were imaged with echocardiography and longitudinal, circumferential, and rotational strains were determined using speckle-tracking. Diastolic strain rate was also determined. Patient demographics and echo-derived flows, volumes, and pressures were recorded. Results. Peak longitudinal and circumferential strain was globally reduced in patients (p < 0.001), when compared to controls. The patients attained peak longitudinal and circumferential strain at a consistently later point in systole than controls. Rotational strains were not different in most LV regions. Early diastolic strain rate was significantly reduced in the patients (p < 0.001). LV mass and wall thickness were significantly increased in the patients; however ejection fraction was preserved and stroke volume was diminished (p < 0.001). Conclusions. This study shows that patients with HFpEF have reduced early diastolic strain rate and reduced peak strain that is regionally homogeneous and that they also utilize a longer fraction of systole to achieve peak axial strains.  Heart failure with a preserved ejection fraction (HFpEF) now accounts for half of patients seen by physicians who have clinical heart failure symptoms . EpidemiThere is great difficulty in translating these detailed experimental findings into an understanding of HFpEF in humans. Several randomized controlled clinical trials –8 examinEchocardiography is readily available to even the most ill patients with heart failure and can be accomplished in reasonable times at the location where the patients are treated. What is not known is whether these detailed measurements of heart motion are sufficiently accurate and sensitive to the changes in the heart muscle that occur with HFpEF to shed light on regional or even molecular mechanisms. In this paper we analyze the results of regional speckle tracking measurements of longitudinal, circumferential, and rotational strains in patients with HFpEF and in a control population. The magnitude of the error seen in the speckle tracking echo strains is quantified. The time-varying pattern of strains for the entire cardiac cycle is then examined to gain information about the mechanism underlying LV dysfunction in HFpEF. The longer term goal of this work is to determine whether progressively detailed and validated measurements of LV wall strains in a larger subset of patients with HFpEF can provide evidence supporting hypothesized molecular mechanisms of HFpEF. For example, it may be possible to distinguish between increased Titin N2B terminal spring stiffness and increased collagen stiffness through distinctive resulting patterns of LV motion.Ten patients with diagnosed HFpEF were enrolled in the study. Each patient had stable heart failure symptoms and was in New York Heart Association (NYHA) Classes II-III. We enrolled patients who met the criteria for HFpEF published by Vasan and Levy and  who wereThe Institutional Review Board of the University of Nebraska Medical Center approved the study protocol. All procedures performed were in accordance with the committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from the volunteers and patients before their addition to the study.A standard echocardiography protocol was utilized. Apical, mid, and basal short axis (SA) regions were scanned using a high frame rate (70–80 frames/s) second harmonic B-mode transducer (transmit/receive 1.4/2.8 MHz) with a Phillips S5-1 ultrasound probe with Hpen on a IE33 echocardiography machine .The long axis (LA) images were standard four-chamber (AP4), three-chamber (AP3), and two-chamber (AP2) views of the LV. These images represent sections in planes orientated at approximately 60° angles from each other. The following definitions were assigned to the SA imaging planes: at the basal level, the mitral valve is in view. The midlevel image was obtained at the upper portion of the papillary muscles. At the apical level, the LV cavity alone is visualized with no papillary muscles. The imaging planes and regions are shown schematically in ECG gating was employed for each image view and two heartbeats were obtained. Customized software (Phillips QLab 8.4) on a personal computer workstation was used for subsequent off-line analysis of ventricular geometry and strains obtained by speckle tracking after image acquisition.The SA and LA images were analyzed using software designed to compute cardiac motion and strain components (Phillips QLab 8.4). Endocardial and epicardial borders were manually selected on a reference image of each SA and LA view. Borders were selected on a still frame of the heart in end systole. Each SA image was subdivided into six circumferential regions: anterior (A), anterior septal (AS), inferior septal (IS), inferior (I), inferior lateral (IL), and anterior lateral (AL) . Each LAFor longitudinal strain, the B, M, and AP regions were obtained for each patient. For circumferential strain, the six regions of A, AS, IS, I, IL, and AL were combined into 3 groups based on their level of acquisition: basal, mid, and apical. The same was done for regional rotation.Each region produced strain or rotation over two heartbeats. The data were then normalized to a single cardiac cycle, eliminating the variability in time with multiple patients. The strain data were then subdivided into twenty-five fractions of one cardiac cycle and each patient's average for strain within that fraction contributed to an overall average for strain at that point for the study group. Eleven subjects for the control group and ten subjects for the diastolic dysfunction group contributed to each of the twenty-five fractions of a single cardiac cycle.E/E′) + 2, where E/E′ is the ratio of the early (E) ventricular filling velocity to (E′) the longitudinal displacement of the mitral annulus /(3/25) and is computed similarly to circumferential strain . The endTo test whether HFpEF patients demonstrate delayed time to peak systolic strain, the time to peak systolic strain was computed as the percentage of the cardiac cycle to reach peak systolic strain from end diastole. Because HFpEF and controls had different heart rates we used data from Weisdorf and Spodick  and Mertt-test if the variables were normally distributed and the Mann-Whitney U test if not normally distributed. Chi square was employed for categorical data. The same procedure was employed to test hemodynamic and geometric data between groups. A p value less than 0.05 was considered statistically significant. The data were fully accessible to the authors of this paper, who take full responsibility for the integrity of the data.Two sample comparisons of the control and HFpEF strain data were performed using The study included 14 women and 7 men with a median age of 50 years and a range of 23–71 years. There were more women in the control group, while the patients with HFpEF were evenly split. The HFpEF patients were older than the controls and they also had a higher frequency of hypertension, diabetes, and hyperlipidemia. Examples of echocardiography images from a single control patient are displayed in A full echocardiographic examination was performed for each of the patients .p < 0.01) while EF is preserved and stroke volume is reduced (p < 0.01). VTI cardiac index is similar because mean HR is increased in HFpEF patients.Utilizing the fitted ellipsoidal ED and ES patient-specific models defined in , LV massp < 0.001). There is a 4.5% to 9.1% increase in longitudinal strain for the control patients when compared to the diastolic dysfunction patients by region . There is a 2.5% to 6.6% increase in circumferential strain for the control patients when compared to the HFpEF patients by region . The average circumferential SRed for controls was 38.8 ± 13.2%/cardiac cycle and for HFpEF it was 18.8 ± 3.9%/cardiac cycle (p = 0.005).The average longitudinal SRed for controls was 35.5 ± 1.6%/cardiac cycle and for HFpEF it was 18.5 ± 8.5%/cardiac cycle  to a HR of 78 (HFpEF) is 1.13. Therefore each time to peak systole for the control patients was normalized by this factor.Time to peak longitudinal strain was uniformly delayed in HFpEF and the time to peak rotation was delayed at most locations, but time to peak circumferential strain was in general not prolonged .This study demonstrates that the magnitude of longitudinal, circumferential, and rotational strains during systole is reduced in HFpEF when compared with controls. The time to reach peak systole is reduced in the longitudinal direction and in rotation, but not in the circumferential direction. Early diastolic longitudinal and circumferential strain rate is reduced in HFpEF. Large variability in regional strain among both patients and controls is evident, although the consistency of the findings from base to apex indicates a substantial reduction in both the magnitude of peak longitudinal and circumferential strain and a delay in achieving peak systolic strain in HFpEF. The delay in achieving peak systolic strain and the difference in magnitude of the peak strains are greater in the longitudinal strain components than in the circumferential or rotational strains.Previous studies demonstrated similar reduction in peak circumferential and longitudinal strains , 18. In As found in other studies, rotational strains are less affected than longitudinal and circumferential strains in HFpEF patients. Rotational strains reported here are of much lower magnitude than previously published because the apical region considered here is nearer to the midventricular level than the true apex and because data for LV free wall and septal regions were lumped together. The rotation of the septum is known to be less than the LV free wall. Nevertheless, this study did not show substantial differences in absolute magnitude of rotation between HFpEF and controls but did suggest differences in time to reach peak rotation.We utilized a small population of HFpEF patients (ten) to allow detailed speckle tracking strain analysis compared with a true control group . The HFpEF group is a similarly relatively homogeneous group of heart failure patients reflecting a typical population seen in clinical practice. They have all of the features typically identified with HFpEF patients: they have a high incidence of hypertension, being overweight, half of the patients have diabetes, and more women are included than a typical population of HFrEF patients. All HFpEF patients have elevated diastolic filling pressures with estimated left atrial pressure (18 versus 10) and mean PA pressure (28 versus 13) more than double the controls. The group was selected so that all patients would have Grade II or more diastolic dysfunction by conventional echo criteria. By clinical criteria the patients have heart failure symptoms and all are in NYHA Class II or III and mean BNP level is substantially elevated.Strain values at each time period show substantial variability marked by the standard deviations of the measurements. This variability arises from variability that undoubtedly occurs from subject to subject in strains based on their age and sex , from thThe relationship between changes in passive and active biophysical properties of the myocardium and the resulting LV displacement and strain fields is complex, because the deformation of the LV is strongly dependent on its dimensions and geometry, and on the preload and afterload to which it is subjected. Mathematical models for LV mechanics provide a potentially useful tool for interpreting observations of LV deformation in terms of myocardial biophysics. We previously developed a simple dynamic model of the LV and examined the effects of muscle parameters and circulatory system variables  on the time course and magnitude of strain generation . For simPrevious studies have demonstrated a reduction in systolic strains in HFpEF patients . The par


Both BNP and sST2 were associated with NYHA class but sST2  was more accurate to identify asymptomatic patients or those who developed symptoms during follow-up. sST2 was independently related to left atrial index (p<0.0001) and aortic valve area . A modest correlation was found with BNP . During follow-up, 29 asymptomatic patients (34%) developed heart failure symptoms. With multivariable analysis, peak aortic jet velocity  and sST2 level  were independent predictors of cardiovascular events. In AS, sST2 levels could provide complementary information regarding symptomatic status, new onset heart failure symptoms and outcome. It might become a promising biomarker in these patients.B-type natriuretic peptide (BNP) is often used as a complementary finding in the diagnostic work-up of patients with aortic stenosis (AS). Whether soluble ST2, a new biomarker of cardiac stretch, is associated with symptomatic status and outcome in asymptomatic AS is unknown. sST2 and BNP levels were measured in 86 patients  with AS (<1.5 cm Aortic stenosis (AS) is the most common valvular heart disease in western countries. Risk stratification in asymptomatic patients and identifying characteristics of poor prognosis in symptomatic subjects have become key elements in the evaluation of AS –3. Aorti2) and preserved left ventricular (LV) ejection fraction (>50%) examined at our Heart Valve Clinic, CHU of Liège. All enrolled patients agreed to participate in our blood sample collection (Biobank) for valvular heart disease. The institutional review board  approved the protocol and all patients gave written informed consent. Demographics and clinical data were recorded in our Institutional electronic medical record at the time of initial visit in the echo lab. Use of cardiac medications, laboratory results, and symptomatic status at the time of the initial echocardiogram were recorded. Absence of symptoms was confirmed by a normal exercise testing. None of the patients had concomitant moderate or severe valvular conditions other than AS, previous valve surgery, complex congenital heart disease, supravalvular or subvalvular aortic stenosis, hypertrophic cardiomyopathy, plasma creatinine level >13 mg/dL, significant arrhythmia, acute and chronic inflammatory disease.The present study consisted of patients with moderate to severe AS  in all patients. All Doppler-echocardiographic recordings were stored in digital format on a dedicated workstation for off-line subsequent analysis. All echocardiographic measurements were performed as previously described by our group. Of note, LV stroke volume was calculated using both the Doppler  and the volumetric  methods. Moreover, multiple transducer positions were used to record peak aortic jet velocities. The highest transaortic velocity was used for tracing of the time-velocity integral and to calculate pressure gradients. For each measurement, at least two cardiac cycles were averaged. The peak E-wave of the mitral inflow was measured using pulsed-wave Doppler. Tissue Doppler imaging with pulsed-wave Doppler at the level of septal and lateral mitral annulus was used to measure e’ velocities. The average of septal and lateral mitral annulus e’ peak velocity was used to calculate the E/e’ ratio.® ELISA, R&D Systems, Minneapolis, MN) according to manufacturer’s instructions. The inter- and intra-assay variation was 6% and 5%, respectively.Venous blood samples for BNP and sST2 measurements were drawn before echocardiography, after 10 minutes of supine rest. Chilled ethylenediaminetetraacetic acid tubes were centrifuged immediately at 1000 x g (4°C) for 15 minutes. Separated plasma samples were processed for BNP measurements by immunoassay . The inter- and intra-assay variation was 5% and 4%, respectively. The assay detection limit was 1 pg/ml. A predictive risk score, including BNP, gender and aortic valve peak velocity, was calculated for each patient according to the recent work of Monin et al . The ratFollow-up information was obtained from interviews with the patients, their relatives or their physicians every six to twelve months, according to current guidelines ,5. The b2 test, or Fisher exact test as appropriate. Correlations between echocardiographic data and biomarkers were assessed with linear regressions. Independent predictors of biomarker levels were obtained with the use of stepwise multiple linear regressions. Stepwise logistic regression analysis was used to determine the predictors of symptomatic status. Probabilities of end point-free survival were obtained by Kaplan-Meier estimates for the 2 groups and then compared by a 2-sided log-rank test. Cox proportional-hazards models were used both in individual and multivariable analyses to identify the independent predictors of the occurrence of end-points. Variables with a univariable value of p<0.10 were incorporated into the multivariable models. The selection of variables included in the multivariate model was performed with a special care. To avoid colinearity among a subset of several variables measuring the same phenomenon , we entered in the multivariate models the variable that had the strongest association with event on univariable analysis. Values of p<0.05 were considered significant. Receiver-operator characteristic (ROC) curve analysis was performed to determine the cut-off values that best distinguished the issue  (AUC: Area under the curve). All statistical analyses were performed with STATISTICA version 10 .Data are given as mean values ± standard deviation (SD); categorical variables are described as number and percentages. Differences between groups were analyzed for statistical significance with the 1-way analysis of variance (ANOVA), χOf the 86 enrolled patients, 27 (31%) were classified as symptomatic at baseline (i.e. inclusion visit) . PatientCompared with the 59 (69%) asymptomatic patients, symptomatic patients at study entry did not differ in gender and presence of risk factors but were older (p = 0.03), had higher aortic pressure gradients (p<0.001), smaller aortic valve area (p<0.001) and higher BNP (p<0.001) and sST2 levels (p = 0.006) . BNP and2 = 0.32) were correlated with sST2 levels. Left atrial index (p = 0.025) and E/e’  were determinants of BNP. In asymptomatic patients, mean aortic pressure gradient and E/e’ were correlated with BNP, whereas aortic valve area, LV mass, and left atrial size were correlated with sST2. E/e’  was the only independent determinant of BNP. Aortic valve area (p = 0.006) and LV mass (p = 0.004) were independent determinants of sST2 (model R2 = 0.27).In the overall population, plasma levels of BNP and sST2 were correlated with the severity of AS, the degree of LV hypertrophy, the diastolic burden  and with the LV ejection fraction . sST2 leIn the group of asymptomatic patients, those who experienced events (29 patients) during follow-up tended to be older (p = 0.086), had more severe AS (higher aortic peak jet velocity (p<0.001), smaller aortic valve area (p = 0.001)), larger left atrium (p = 0.011), higher BNP (p = 0.013) and sST2 (p = 0.001) levels . For theThe main findings of this study are: (1) sST2 appears to be a new promising biomarker to separate symptomatic from asymptomatic patients with AS, (2) sST2 is related to AS severity and the extent of diastolic burden as assessed by the left atrial area, (3) high sST2 levels are likely associated with outcomes in asymptomatic AS.In the present study, there was a good association between the symptomatic status and plasma levels of sST2. Interestingly, sST2 levels gradually increased with the NYHA class. Conversely, although BNP was univariately associated with the NYHA class and correlated modestly with sST2 levels, it did not emerge as an independent determinant of the symptomatic status. Although adjusted for age and sex, BNP ratio , 21 did The prognostic power of circulating sST2 has been demonstrated in patients with acute myocardial infarction or in the context of acute dyspnea with or without heart failure ,18, 25. We acknowledge that our study has some limitations. Despite the examination of a reasonable number of patients with AS, the subgroup of symptomatic AS patients remained relatively small. sST2 measurements were not repeated during the follow-up period, and therefore the prognostic value of serial sST2 changes could not be assessed. The relationship between ST2 and global and regional myocardial function was not assessable. In order to confirm the association of sST2 with AS, further studies that would analyse serial changes of sST2 during patient follow-up are required.


Objective. Stroke alters cortical excitability both in the lesioned and in the nonlesioned hemisphere. Stroke recovery has been studied using transcranial magnetic stimulation (TMS). Spontaneous brain oscillations and somatosensory evoked fields (SEFs) measured by magnetoencephalography (MEG) are modified in stroke patients during recovery. Methods. We recorded SEFs and spontaneous MEG activity and motor threshold (MT) short intracortical inhibition (SICI) and intracortical facilitation (ICF) with navigated TMS (nTMS) at one and three months after first-ever hemispheric ischemic strokes. Changes of MEG and nTMS parameters attributed to gamma-aminobutyrate and glutamate transmission were compared. Results. ICF correlated with the strength and extent of SEF source areas depicted by MEG at three months. The nTMS MT and event-related desynchronization (ERD) of beta-band MEG activity and SICI and the beta-band MEG event-related synchronization (ERS) were correlated, but less strongly. Conclusions. This first report using sequential nTMS and MEG in stroke recovery found intra- and interhemispheric correlations of nTMS and MEG estimates of cortical excitability. ICF and SEF parameters, MT and the ERD of the lesioned hemisphere, and SICI and ERS of the nonlesioned hemisphere were correlated. Covarying excitability in the lesioned and nonlesioned hemispheres emphasizes the importance of the hemispheric balance of the excitability of the sensorimotor system. The motor system is a dynamic network of cortical and subcortical areas interacting through excitatory and inhibitory circuits, modulated by somatosensory input. The network balance is disturbed after stroke –3. ModifMotor threshold (MT), that is, the minimal TMS intensity eliciting motor evoked potentials (MEPs), is related to membrane excitability as it is influenced by drugs affecting neuronal ion channels. Paired pulse TMS (PP-TMS) reveals short-interval intracortical inhibition (SICI), related to the activation of GABA-A receptors and intracortical facilitation (ICF) attributed mainly to glutamatergic NMDA receptor activation . In acu Reduction of beta ERS, however, correlated with clinical improvement after physiotherapy of patients with chronic stroke [Finger movements and median nerve  or fingec stroke . Movemenc stroke .The hand representation in the somatosensory cortex (S1), estimated by somatosensory evoked fields (SEFs), is the largest one month after stroke and its increase was correlated with the affected hand function . In TMS We recorded both nTMS and MEG from patients during stroke recovery. We hypothesized to see correlations between ERD and MT related to the early cortical excitability and between ERS and SICI, both attributed to GABA-A-related processes. Moreover, we expected that ICF, reflecting glutamatergic activity, would correlate with the somatosensory modifications in MEG, as glutamate is associated with late somatosensory plasticity .http://dx.doi.org/10.1155/2015/309546). Only the features needed for interpretation of the present results are described.MEG and nTMS were recorded from thirteen patients , with first-ever ischemic stroke in the middle cerebral artery territory one (T1) and three months after stroke (T2). Hand function was impaired in all patients. Six patients had a subcortical and seven patients had a subcorticocortical or cortical stroke . At T1, An eXimia navigated magnetic stimulator with a coplanar figure-of-eight coil of 70 mm wing radius  was used for nTMS. Patients' MRIs, required for navigation, were scanned at T1 and used also at T2.The site eliciting the largest MEP amplitude in first dorsal interosseous muscle was located. The resting MT was determined from this site as described in . The sitMEG during rest and tactile stimulation of the thumb (D1), index (D2), and little finger (D5) were recorded with a 306-sensor neuromagnetometer  in BioMag laboratory, right before the nTMS measurement. The interfering signals were suppressed by Maxfilter software . The sigTime-frequency representations (TFR ) in the xyz-space between the equivalent current dipoles (ECDs) of the earliest responses to D1 and D5 stimulation [For SEFs, about 120 responses were averaged for stimulation of D2 (ISI 3005 ms), and D1 and D5 (ISI 1005 ms) in separate sessions. The size of the hand representation in the SI was determined by calculating the Euclidean distance in mulation . The ampmulation  were useN = 32) suggested by the four prior hypotheses . The significance level was set at p < 0.05. We also present significances of correlation values without multiple comparisons and supply all correlation coefficients and corresponding p values . Spearman's correlation coefficients were calculated between nTMS and MEG parameters. Multiple comparison correction was carried out according to the number of tests  and in 10 patients at T2 . The MTs in the LH and NH correlated strongly both at T1  and at T2 .In the LH, MEPs were found in 11 patients both at T1 and at T2 and were present in the NH in all patients. Group average MTs did not change between measurements or hemispheres. Individual MT values are given in Supplementary Table 1. MT was higher for LH than NH in 9 patients at T1  in 5 patients at T1 and in 3 patients at T2. SICI values did not correlate significantly between the hemispheres at T1 or T2.r = .62; p < .05) but not at T2 (Supplementary Table 2).PP12ms stimulation of LH facilitated MEPs (ICF) in 10 out of 11 patients at T1 and in all patients at T2. In NH, ICF was induced in all patients at T1. At T2, ICF was not observed in 4 patients. MEP amplitudes elicited by PP12ms stimulations were correlated between the LH and NH at T1 (p < .05); at T2, the difference was nonsignificant. SEFs from both hemispheres were detected in 12 patients at T1 and in all patients at T2. They were smaller in the LH than NH at T1  but not at T2. The SI hand representation area was larger in the LH than NH at T1 (12 ± 3 mm versus 10 ± 3 mm p < .003) but not at T2 (Supplementary Table 3).ERD started 140 ± 10 ms after tactile stimulation and peaked at 250 ± 10 ms. The subsequent ERS started at 520 ± 40 ms and peaked at 900 ± 70 ms. At T1, ERD was absent in one patient and ERS in two patients in the LH; ERS was missing from the NH in one patient. At T2, the ERD was present in every LH whereas ERS was absent in two. Both were present in all NHs. ERDs did not differ between the hemispheres. ERS was smaller in the LH than NH at T1 , indicating that small ERD was associated with a high MT . However, the MT of the LH correlated with the ERD of NH , and the MT of the NH correlated with ERD of the LH , suggesting that high MT was associated with a small ERD in the opposite hemisphere at T2 , indicating that strong ERD in the LH was associated with a strong SICI in the NH. SICI in the LH was correlated also with the SI amplitude of the LH , indicating that small SI amplitude was associated with a weak SICI ; if ICF was strong, the SI amplitude was small. In addition, ICF in the NH correlated  with the SI finger representation area of the LH; this correlation remained significant also after Bonferroni correction  with the SI finger representation area of LH at T2; high ICF at T1 resulted in a small hand representation area at T2 . Interhemispheric correlations of SICI were not limited to ERS. One reason for this may be that various GABA-A receptor subtypes contribute to SICI. Nonselective GABA-A receptor activators modify SICI whereas the GABA-A1 receptor specific zolpidem did not . NonseleCorrelations between nTMS parameters and MEG ERD/ERS were stronger at T2 than at T1. Analogously, most TMS intracortical excitability measures did not correlate with the hand function acutely but did so 3 months after stroke , emphasiICF correlated with SI hand area size at T2. As ICF is attributed mainly to glutaminergic mechanisms, glutamate may contribute to stroke-induced plasticity. Somewhat surprisingly, high ICF at T1 correlated with small SI hand area at T2 ; thus, tSeveral correlations emphasized interhemispheric connectivity see . For exa affected hemisphere and nTMS indices in the unaffected hemisphere were correlated with the motor performance of the affected hand , 24 affe decreases postmovement beta ERS [ increases postmovement beta ERS [ increased [ prolonged, indicating prevailing inhibitory cortical tonus [ERD in the 8–22 Hz band may reflect downregulation of intracortical inhibition in the human motor cortex, as TMS delivered during ERD is associated with increased MEP amplitudes and reduced SICI . Howeverbeta ERS , and intbeta ERS . Beta ERbeta ERS . In linencreased , 45, andncreased , is prolOur results suggest that some TMS and MEG excitability measures reflect the activity of the same transmitter systems. However, high MT and absence of ERD/ERS may also correlate because of severely affected sensorimotor connections between the periphery and the cortex. We detected SEFs in 12/13 patients and MEPs in 11/13 patients already at T1, indicating that both somatosensory and motor pathways were conveying signals. Motor function can be maintained despite significant damage to the corticospinal tract, as estimated from MT of stroke patients [The limitations of our study include the small size of the patient group as the precise features of structural and functional changes may differ among the patients. Cortical excitability is modified differently in cortical and subcortical strokes , 47. ThiICF and SI response amplitude and area size, MT and the ERD of the hemisphere harboring the stroke lesion, and SICI and ERS of the nonlesioned hemisphere are correlated in stroke patients. Numerous correlations of the excitability parameters between the LH and NH emphasize the importance of the hemispheric balance of the excitatory-inhibitory properties of the sensorimotor system in analyzing the stroke-related dysfunction during stroke recovery.Supplementary material contains individual motor threshold values in both hemispheres of each patient at T1 (1 month) and T2 (three months) after the stroke (Table 1), mean values and standard deviations of the nTMS parameters at T1 and T2 (Table 2) and mean values and standard deviations of the MEG parameters at T1 and T2 (Table 3).


To identify predictors and the optimal time point for the early prediction of the presence and severity of spasticity in the upper limb 12 months poststroke.In total, 117 patients in the Gothenburg area who had experienced a stroke for the first time and with documented arm paresis day 3 poststroke were consecutively included. Assessments were made at admission and at 3 and 10 days, 4 weeks, and 12 months poststroke. Upper limb spasticity in elbow flexion/extension and wrist flexion/extension was assessed with the modified Ashworth Scale (MAS). Any spasticity was regarded as MAS ≥1, and severe spasticity was regarded as MAS ≥2 in any of the muscles. Sensorimotor function, sensation, pain, and joint range of motion in the upper limb were assessed with the Fugl-Meyer assessment scale, and, together with demographic and diagnostic information, were included in both univariate and multivariate logistic regression analysis models. Seventy-six patients were included in the logistic regression analysis.Sensorimotor function was the most important predictor both for any and severe spasticity 12 months poststroke. In addition, spasticity 4 weeks poststroke was a significant predictor for severe spasticity. The best prediction model for any spasticity was observed 10 days poststroke . The best prediction model for severe spasticity was observed 4 weeks poststroke .Reduced sensorimotor function was the most important predictor both for any and severe spasticity, and spasticity could be predicted with high sensitivity and specificity 10 days poststroke. Whether early assessments of upper limb function and impairments can predict the occurrence and degree of upper limb spasticity 12 months poststroke with good accuracy is uncertain. The optimal time for early prediction of upper limb spasticity 12 months poststroke is also unknown.12 This information is of clinical relevance, as patients with an increased risk of developing spasticity-related impairments, complications, and increased disability may be identified.13 The study aims were to identify predictor variables and the optimal time for early prediction of any spasticity and severe spasticity in the upper limb 1 year poststroke.Upper limb spasticity has been found to be associated with reduced arm function and low levels of independence, and with a 4-fold increase in direct care costs during the first year poststroke.14 All included patients had ischemic or hemorrhagic stroke15 for the first time, were over 18 years old, and had impaired upper extremity function, which was assessed at day 3 with the Action Research Arm Test (ARAT) (0–57)16 and defined as <57 points. The study sample size estimation (n = 88) for SALGOT was to determine a medium change of 6 points (10%) on ARAT, with a power of 0.8 and a significance level of 0.05. With an expected dropout rate of 30%, the aim was to include 120 patients.14All patients with first-ever stroke in an 18-month period in 2009–2010 who were admitted to the largest of 3 acute stroke units at the Sahlgrenska University Hospital, Gothenburg, Sweden, within 3 days after stroke onset were eligible for consecutive screening for inclusion in the present study, which was a part of the Stroke Arm Longitudinal Study at the University of Gothenburg (SALGOT). In the SALGOT study, the recovery of upper extremity function was investigated in a nonselected sample during the first year poststroke.www.clinicaltrials.gov (NCT 01115348).Study approval was provided by the Regional Ethics Committee of the Western region of Sweden (Registration number 225/08), and written informed consent was obtained. The study is registered at 14 A majority of the assessments were performed at the university hospital. If traveling was not possible for the patient, the assessments were conducted in the patient's home, nursing home, or rehabilitation unit.In SALGOT, the patients were assessed 9 times during the first year: at admission; at 3 and 10 days; at 3, 4, and 6 weeks; and at 3, 6 and 12 months poststroke. In the current study, data from admission, 3 and 10 days, 4 weeks, and 12 months were used. Predominantly, the assessments were carried out by 3 physiotherapists and were performed according to a standardized protocol.17 and ischemic stroke was classified after cause of lesion using the Trial of Org 10172 in Acute Stroke Treatment criteria.18 The initial severity of stroke and arm paresis was assessed with the 0- to 42-point ordinal NIH Stroke Scale (NIHSS) and the NIHSS arm subscale (0–4), respectively.19 NIHSS arm was treated as a categorical variable with 0 as the reference category.Clinical characteristics and assessments routinely registered at admission during the acute stage of stroke were selected as potential predictor variables . Stroke localization was classified using the Oxfordshire Classification20 The FMA-UE (sections A–D) includes 33 active motor function tests, where a higher score indicates a better performance (0–66). The nonmotor domains of the same scale (sections H–J) were used to assess sensation (0–12), joint pain (0–24), and range of motion (ROM) during passive joint motions (0–24); lower scores indicate reduced sensation, more pain, and reduced ROM, respectively. Spasticity in elbow flexors, elbow extensors, wrist flexors, and wrist extensors were assessed with the 6-level modified Ashworth Scale (MAS).21 The original MAS categories were reordered into integers between 0 and 5, to incorporate the score 1+. MAS were dichotomized, and spasticity was considered to be present if the MAS score was ≥1 in any of these muscle groups.Common clinical assessment scales of sensorimotor impairments assessed at 3 and 10 days and 4 weeks poststroke were selected as potential predictors. Sensorimotor function in the upper limb was assessed with the motor function part (sections A–D) of the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE).22At 12 months poststroke, spasticity was reassessed in a similar way as previously. Any spasticity was considered if the MAS score was ≥1, and severe spasticity was considered if the MAS score was ≥2 in any of the muscle groups.r > 0.8), one was omitted before multivariate logistic regression analysis. The multivariate logistic regression analyses were used to predict the presence of (A) any spasticity and (B) severe spasticity at 12 months poststroke. In both (A) and (B), 4 models (A1–A4 and B1–B4) were found and compared . Univariate logistic regression analyses were used to assess the relationship between the potential predictor variables and the outcome variable. The predictor variables were tested for correlations, and when 2 variables had a high correlation (compared . The crip < 0.05) were included in the final model. To control for possible nonlinearity between summed ordinal predictors and the dependent variable, a multivariate model with the squared predictor variables (FMA-UE2 and Sensation2) was tested. Nonsignificant associations were interpreted as nonlinearity not shown.23 The results are presented with unstandardized coefficients, p values, and odds ratios with 95% confidence intervals (95% CIs).24 The sensitivity (%), specificity (%), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and the corresponding 95% CI for each of the models was calculated using MedCalc for Windows, version 12.7.7.0 . All other statistical calculations were performed using IBM SPSS statistics 21.0 . The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.26In the multivariate logistic regression analysis, the enter method was used stepwise and nonsignificant variables were removed manually one at the time, to ensure that only significant variables (p < 0.001), and fewer of them had hemorrhagic infarction .In total, 763 patients were admitted to the stroke unit during the inclusion period, 117 of whom were included in the study and assessed at day 3 (SD 1). There were no significant differences between the participating and nonparticipating patients in terms of sex or NIHSS score. The nonparticipating patients were significantly older  and included in the logistic regression analysis. The 2 main causes for dropout were death (n = 14) and study withdrawal (n = 7). The clinical characteristics of the 76 patients included in the logistic regression analysis are shown in At 3 and 10 days and 4 weeks, 24%, 43%, and 46% of the 76 patients were assessed with any spasticity, respectively. At 12 months, 46% and 29% were assessed as having any spasticity and severe spasticity, respectively.Neurology® Web site at Neurology.org. The multivariate logistic regression analysis results are presented in 2) was not significant in models A2–A4, and nonlinearity could not be shown.The univariate logistic regression analysis for all potential predictor variables for any spasticity and severe spasticity is presented in tables e-1 and e-2 on the 2 and Sensation2) were not significant predictors in any of the models B2–B4, thus nonlinearity could not be shown.The results from multivariate logistic regression models B1–B4 are shown in The present study demonstrated that any spasticity was best predicted with variables collected at day 10 poststroke and severe spasticity was best predicted with variables collected 4 weeks poststroke. Lower sensorimotor function score, as identified with the FMA-UE, consistently and significantly predicted both any spasticity and severe spasticity at 12 months poststroke. Age at stroke onset was a significant predictor 4 weeks poststroke, with higher age associated with reduced probability for spasticity. The presence of upper limb spasticity 4 weeks poststroke was a significant predictor for severe spasticity.12 However, none of the previous studies used the FMA-UE to assess sensorimotor function, and thus, a direct comparison cannot be made with those studies. Additionally, none of the former studies compared different prediction models for spasticity at 12 months poststroke based on the assessments at different time points relatively early after stroke onset, as was performed in the present study. Predicting upper limb spasticity with a relatively high accuracy based on early assessments may have high clinical relevance, as patients with an increased risk of developing spasticity-related impairments may be identified early and monitored more closely in order to implement appropriate interventions.These findings support previous studies reporting paresis and reduced ADL function to be significant predictors for spasticity poststroke.22 where more severe spasticity was found in younger patients 3 months poststroke, but not 18 months poststroke. Muscle force generation from tendon reflexes has been found to be slower and weaker with increasing age27 and if this also is the case for tonic reflexes associated with spasticity, spastic responses may be weaker in older patients.In the present study, patients with higher age were predicted to have reduced probability for spasticity. This finding may be in accordance with a previous study12 There may be several reasons for this discrepancy; for instance, there were methodologic differences between the studies, as the Tone Assessment Scale was used to assess spasticity, and spasticity and weakness were assessed in both arms and legs12 as opposed to only upper limb spasticity and sensorimotor function in the present study. An association between smoking and severe spasticity has been found previously,12 which could not be confirmed here. The authors discussed that their model, which included smoking, had an event per variable of 7, compared to the recommended minimum of 10.28In the present study, there was no association between the side of weakness and spasticity 1 year after stroke, as described previously.Model B1 showed that patients with lacunar stroke had a lower OR for severe spasticity than those with other stroke locations. Therefore, the Oxford categories were included in model B2 to check for stroke location as a possible predictive factor. No association between stroke location and spasticity was observed in model B2.29 Therefore, spasticity may be an unstable impairment during the first months, before a more stable and manifest impairment is observed. A recent study based on the same study population supported this finding,5 as the authors found that patients changed both from no spasticity to any spasticity and vice versa during the first months poststroke.Presence of upper limb spasticity in the assessments during the first month was not a significant predictor for any spasticity at 12 months poststroke. Spasticity at 4 weeks poststroke was a significant predictor only for severe spasticity at 12 months. There may be both neurologic and muscular causes for this observation, as the tonic stretch reflexes may increase during the first 3 months, and intrinsic muscle changes may occur later.13 Patients at risk can be followed more closely, and spasticity may be treated both pharmacologically and non-pharmacologically.30 It is uncertain whether early treatment reduces spasticity in the long term. However, it has been well-established that such treatments have led to significant improvements in spasticity-related impairments, motor function, and quality of life among patients poststroke.30–33The clinical implications of the current study are mainly within 2 areas. First, the assessment of motor function at an early stage, either with the NIHSS at admission or with the FMA-UE, may give a good indication of the probability of a patient developing spasticity 12 months poststroke. At 3 days poststroke, the sensitivity and specificity of the prediction models were 85% and increased further at day 10. From a clinical perspective, the assessment of sensorimotor function and the early identification of patients at risk of developing spasticity and in particular severe spasticity may be important. Spasticity has been found to be associated with pain, reduced range of motion, and reduced motor function, which can have a negative impact on the functional ability of the patient.34 as spasticity and related impairments may develop over months.The second clinical implication may come from the finding that the assessment of spasticity at day 3 or 10 could not predict spasticity after 1 year. Although the univariate logistic regression showed a significant association between spasticity at day 10 and spasticity 12 months poststroke, this association was lost in the multivariate regression analysis, as the FMA-UE was a much stronger predictor. Only after 4 weeks was the presence of spasticity a predictor, as patients with spasticity had a 30 times higher OR for severe spasticity 12 months poststroke than those without spasticity. Additionally, the chance of developing severe spasticity 1 year after stroke was very low if the assessment of spasticity at week 4 showed no spasticity. Consequently, there was a time point between 10 and 28 days poststroke at which spasticity became a predictor for severe spasticity, indicating that spasticity predominantly emerged and became manifest during this period. Therefore, the clinical value of assessing spasticity in patients much earlier than 4 weeks poststroke to predict long-term severe spasticity may be limited. However, the assessment of spasticity at this time may be important for other purposes. Both of these clinical implications indicate a need for regular and structured follow-ups for patients poststroke21 In the present study, MAS was dichotomized for both any spasticity and severe spasticity, which may be claimed to be arbitrary and not necessarily coincide with important clinical divisions. The dichotomization for any spasticity has shown that patients with spasticity had poorer sensorimotor function, more pain, and reduced ROM than those without spasticity.5The assessment of spasticity may be a limitation as the MAS is an ordinal, clinical assessment scale and not a metric measure of spasticity. However, it does not require any equipment, is easy to apply in different settings, is frequently used, and has relatively good intrarater reliability.35–37 The unidimensional hierarchy of the FMA-UE has been demonstrated both in acute and chronic stroke38 and as nonlinearity of the FMA-UE could not be shown, we chose to use the FMA-UE in the analysis.In the current study, the summed score of the ordinal FMA-UE scale was used in the prediction models, which can be a limitation. However, the FMA-UE has been shown to have excellent psychometric properties, to be a valid indicator of motor recovery, and is widely used to indicate stroke severity.The patients in the present study may be regarded as fairly representative for patients with first stroke, with reduced arm function at day 3, living in a western European country, and receiving modern stroke care according to evidence-based practice. The patients in the present study may not be representative of the global population of persons poststroke.


Left ventricular (LV) trabeculation is highly variable between individuals, and prominent trabeculation, or non-compaction, has been considered to be evidence of abnormal cardiac development. The significance of increased trabeculation in asymptomatic healthy individuals with preserved LV systolic function is unknown. The aim of this study was to determine if excessive LV trabeculation in middle aged and older subjects without LV dysfunction or advanced cardiac disease was associated with changes in cardiac volumes and function over the ensuing 10 years.Asymptomatic individuals  from the Multi-Ethnic Study of Atherosclerosis with preserved systolic function at baseline cardiac magnetic resonance (CMR) were assessed. The extent of trabeculation, expressed as the ratio of non-compacted to compacted (NC/C) myocardium was measured on long-axis cine images in the second CMR study 9.5 years after the baseline scan. NC/C ratios were considered in quintiles with top quintile values exceeding published normal thresholds (2.46 - 5.41). We examined associations between maximal NC/C ratio and changes of (body surface area) indexed end-systolic volume (ESVi), indexed end-diastolic volume (EDVi) and ejection fraction (EF) over 9.5 years.2, EDVi decreased by 5.1 ml/m2 and EF decreased by 0.7% .Maximum NC/C ratio ranged from 0 to 5.41. Over 9.5 years, ESVi decreased by 1.3 ml/m2 increase in ESVi, 2.7 ml/m2 increase in EDVi and no change in EF when adjusted for demographic data, risk factors and baseline LV parameters. The changes are clinically irrelevant.Increase in NC/C ratio by one unit (e.g. 1 to 2) was associated with 1.1 ml/mChanges in ESVi, EDVi and EF between quintiles of NC/C ratio are presented in Figure The severity of LV trabeculations in middle aged and elderly asymptomatic individuals without LV dysfunction, advanced coronary artery or significant valvular heart disease is not associated with deterioration in LV volumes or function over the ensuing 10 years. Long-term follow-up of such individuals may not be warranted.National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts  and National Institute of Health (MESA).


Lamin A/C gene mutations can be associated with myocardial diseases, usually characterized by dilated cardiomyopathy and/or arrhythmic disorders. Phenotypic penetrance is age-related but expression is extremely heterogeneous, so that muscular and arrhythmic disease can be present in combination in the same patient, or one phenotypic manifestation can appear earlier than the other or even not become overt for a long time period. From a Patients can be diagnosed as being affected by a cardiolaminopathy as a result of a cardiological workup performed for symptoms of heart failure or for arrhythmic events or can be diagnosed incidentally or during family screening. Family history, physical examination, laboratory findings  and ECG findings are important “red flags” to diagnose a cardiolaminopathy. Patients with cardiolaminopathies may present a wide range of arrhythmic disturbances, which include either bradyarrhythmias  or tachyarrhyhmias , in variable combinations, and with frequent association with left ventricular dysfunction and heart failure Figure . The pre


Social cues facilitate relationships within communities. Zebra finches form long-term stable mate pairs and produce offspring within a multi-family, multi-generational community that can include hundreds of birds. Males use song to communicate in this complex environment. Males sing as part of their courtship display but also abundantly throughout each day, suggesting a role for their vocal signature outside of a reproductive context. One advantage of a vocal social cue is that it can be exchanged when birds are out of visual contact, as regularly occurs in a zebra finch community. Previous works have demonstrated that females hearing song are affected by their social relationship to the bird singing it, and the immediate social context. Here, we probed the question of whether or not the song itself carried social information, as would be expected from the situations when males sing outside of view of the female. We quantified behavioral and neurogenomic responses to two songs we predicted would have distinct “attractive” qualities in adult females housed in either mixed sex or female-only social communities. Our results show that only mixed sex-housed females show distinctive behavioral and neurogenomic responses to attractive songs. These data are consistent with the idea that the acoustic properties of song carry social information, and that the current social situation modulates the neural and behavioral responses to these signals. Animals that live in social environments exchange a variety of cues that enable individuals to establish, maintain, and dissolve relationships. Zebra finches form long-term stable mate bonds within the large multi-family communities they live in. Song is a key component in their social communication. Only males sing. They sing as part of their courtship display but also sing abundantly outside of this context. Females do not sing but are often the recipients of these complex auditory cues.Females use song as part of mate selection, can discriminate their mate's song from a novel song, and are typically affected by the social environment in which they hear song c.f. Here, we asked about the social meaningfulness of song, stripped of environmental context, and presented in standardized, controlled playback conditions. We assayed adult female responses to passive song playbacks to test two hypotheses: 1. social information embedded in the acoustic structure of song is reflected in both neural and behavioral responses to playbacks, and 2. recent social experience alters neural and behavioral responses to song playbacks. We tested two populations of females. All of the birds were raised in normal aviary conditions, but were housed in two different social communities at the time of the experiment. We measured unmanipulated behavioral responses to playbacks of two songs we predicted to have distinct attractive qualities, here termed “Popular” and “Unpopular” because their structure is associated with mate choice preferences. In the same birds, we assayed neurogenomic responsiveness to the two songs experienced in the behavioral paradigm.This study therefore combines the sensitive and selective patterns of genomic activation initiated by hearing song in the auditory forebrain and the fact that perceptual processing is linked to behavioral response Procedures were in accordance with the National Institute of Health guidelines for the care and use of animals for experimental procedures and approved by the University of Chicago Institutional Animal Care and Use Committee (ACUP #72220).Taeniopygia guttata) females, named here for their housing conditions. All birds were raised through adulthood in flight breeding aviaries that housed males and females of all ages. The “Mixed Sex” (MS) birds (n = 12) continued to live in breeding aviaries, in a room that contained 5 such aviaries, through the course of the experiment except when being tested. Five months prior to the start of the experiment, the “Single Sex” (SS) birds (n = 14) were removed from breeding aviaries and placed in an aviary that housed only adult females, in a room that contained only females. SS birds continued to live in this female-only social situation for the duration of the experiment except when being tested. All birds were housed on a 14∶10 light:dark cycle. Water and seed were provided ad libitum.We used two Populations of adult (> Posthatch Day 90) zebra finch  were caught in their respective home aviaries and placed individually into a sound-attenuating chamber that contained a video camera, a light and speakers. Each bird was given 60 minutes to acclimate to the chamber. The birds then heard 30 minutes of song playback of one song, followed by 30 minutes of silence, then a second 30 minute playback period of the second song. Each playback period consisted of one instance of the song, with one bout repeated every 10 seconds (i.e. 6 song bouts per minute). Females were removed from the chamber 15 minutes after the second song playback period ended. We started recording the bird's behavior 10 minutes before the first song playback to capture baseline activity levels.Birds in the two-day experiment  also had a 60 minute acclimation period and 30 minute of song playback with video recording, but playbacks were separated by 24 hours instead of 30 minutes. Birds were returned to their home aviaries between playback sessions. We again recorded the bird's behavior starting 10 minutes before song playback through the 30 minutes of song playback.To ensure that none of the females had previously heard stimulus songs, we chose four from a database of recordings obtained from birds at another university. We created two Song Pairs. Each pair consisted of a Popular and an Unpopular song. Criteria for “popularity” were based on reports that female zebra finches prefer long songs whose bouts  have a large number of different types of syllables Song Pair 1 was comprised of songs 1166 and 12239 . We consWe developed an ethogram to capture the behavioral profile of each bird before and during song playbacks . We usedIn addition to scoring the seven behaviors, we also coded the time of delay to each bird's first behavior. Delay was defined as the duration between song playback onset and the bird's first behavior, which could be any of the behaviors with the exception of look around. This definition of delay, along with the decision to exclude look around as one of the behaviors that would determine the end of the delay, is similar to what Stripling and colleagues (2003) called “response latency” in their song discrimination study.To test the auditory forebrain patterns of the immediate early gene Arc induction in response to the experimental songs without confounds of familiarity, we waited to do song playbacks for catFISH for at least 2 weeks after birds were tested for behavioral responses.For catFISH playbacks, females were removed from their home aviaries and placed individually into sound-attenuating chambers overnight for ∼16 hours. Each female was played one song for 15 minutes, followed by 10 minutes of silence and then 5 minutes of the second song. Song playback periods consisted of a single song bout, repeated once every 10 seconds. Each female heard the same Song Pair and Popular-Unpopular song order as they had in the behavioral experiment. Immediately after the second song finished, females were removed from the chambers and the whole brain was rapidly dissected and flash frozen. Brains were stored at -80°C until use.We collected 8 µm parasagittal sections from the auditory forebrain of experimental birds plus three adult females placed into chambers without song playback as silence negative controls (n = 3). All sections were from the left hemisphere. Auditory forebrain sections 100–300 µm from the midline were processed for FISH zif268, egr-1, ngfi-a, knox24) antisense riboprobes. In the auditory forebrain, ZENK dual label was used as visual aid to cell morphology only. In the MLd, we used it as the measure of auditory experience, as ZENK activation positively correlates with hearing a stimulus, regardless of its novelty or quality TGGAAGAAGTCCATCAAGGC; S primer: TTGCGCCAGAGGAACTGGTC, GenBank Accession # EF076776; We hybridized with both Arc and ZENK  with a 594 nm fluor for 1 hr at room temperature. Slides were then washed in TN and treated with 0.6% H2O2 to exhaust residual peroxidases from the TSA procedure. Sections were washed in TN, incubated for 2 hr at room temperature in a 1∶100 dilution of POD-conjugated anti-biotin primary antibody in block solution, washed in TN, then incubated 1 hour at room temperature in TSA with a 488 nm fluor. Slides were washed in TN, treated with 1∶10000 dilution of DAPI in TN for 2 min, and washed again before coverslipping in aqueous mounting media.For Arc catFISH with ZENK double-label, sections were dried at room temperature, fixed for 7 min in 3% paraformaldehyde (pH 7.4), rinsed 4x in 0.025 M KPBS (pH 7.4) equilibrated in 0.1 M TEA for 3 min, then treated with 0. 25% v/v acetic anhydride in TEA for 10 min. Sections were washed 2x in 2X SSC, then dehydrated serially with ethanol. After drying at room temperature, sections were hybridized 16 hr at 65°C hybridization solution  containing 400 ng each of Arc and ZENK riboprobes. After hybridization, sections were rinsed in 2X SSC to remove coverslips and washed in 0.1X SSC/50% formamide and 0.1X SSC, all at 65°C. Sections were then rinsed in TN , and treated with 0.6% HWe captured three regions of auditory forebrain, caudomedial mesopallium (CMM), dorsal caudomedial nidopallium (dNCM), ventral NCM (vNCM), and an adjacent area of hippocampus (HP) as a within-section staining intensity control . We alsoOn catFISH-processed sections, we manually counted four measures in each auditory forebrain image: total number of cells (DAPI), intranuclear Arc staining, cytoplasmic Arc staining, and double-localized (intranuclear and cytoplasmic) Arc staining. Cell counting was performed blind to the condition of the birds (by SEL). We used the ZENK channel on images to aid identification of cell morphology but because different immediate early genes are not always induced together, all auditory forebrain in situ hybridization quantification was based on Arc label To assess the ovarian status of the birds, we measured the number and size of follicles at the time of catFISH tissue collection . Follicles were categorized as medium, small, or very small based on size and presence or absence of yolk . We originally reserved the “large” class for even larger yolk-filled follicles but none were observed.We used one-way analysis of variance (ANOVA) to examine Paradigm and Song Pair effects . To compare individual normalized behavioral responses, behavioral rates, and delay times between Song Types , and Populations , and the interaction between these variables, we used two-way ANOVA (SAS software version 9.4); Population differences based on Song Type were analyzed with one-way ANOVA. Delay times were non-normally distributed based on Shapiro-Wilk's analysis; we therefore log transformed these data prior to ANOVA testing. We also used multivariate ANOVA (MANOVA) statistics to analyze behavioral measures collectively across Populations (SAS software version 9.4). Normalized cell proportions for each auditory forebrain region were analyzed with two-way ANOVA (SAS software). For MLd, ZENK intensity measures were compared directly for Song Type with one-way ANOVA (SAS software version 9.4). We used one-way ANOVA to test for differences in the abundance of ovarian follicle categories between MS and SS females, and linear regression to test for relationships between ovarian follicle status, Delay times, and catFISH results (SAS software version 9.4).Testing birds on one day or across two days did not significantly affect any behavioral measure  = 0.14, p = 0.72; eating: F = 0.65, p = 0.43; long hop: F = 1.16, p = 0.29; look around: F = 3.03, p = 0.10; preening: F = 3.48, p = 0.09; short hop: F = 2.75, p = 0.11; calls: F = 0.31, p = 0.58) or delay times  = 2.08, p = 0.16). We therefore combined data from the two paradigms for all other analyses.We also compared the behavioral responses and delay times between Song Pairs. We found no differences in behavioral responses  = 0.21, p = 0.65; eating: F = 0.01, p = 0.97; long hop: F = 2.95, p = 0.09; look around: F = 0.13, p = 0.71; preening: F = 0.92, p = 0.34; short hop: F = 3.00, p = 0.10; calls: F = 0.54, p = 0.47) or delay durations  = 0.08, p = 0.78). We therefore only considered the category of Popular and Unpopular in further analyses.We tested for main effects of Population and Song Type, and the Population * Song Type interaction for behaviors in the ethogram. We found no main effects of Population  = 2.10, p = 0.16; eating: F = 0.71, p = 0.41; long hop: F = 1.90, p = 0.18; look around: F = 0.97, p = 0.34; preening: F = 1.32, p = 0.26; short hop: F = 2.72, p = 0.12; calls: F = 3.69, p = 0.07) or Song Type  = 0.38, p = 0.54; eating: F = 0.02, p = 0.89; long hop: F = 1.37, p = 0.25; look around: F = 0.09, p = 0.77; preening: F = 1.72, p = 0.20; short hop: F = 3.61, p = 0.07; calls: F = 1.29, p = 0.27), and no significant interaction  = 3.45, p = 0.08; eating: F = 2.46, p = 0.13; long hop: F = 1.49, p = 0.23; look around: F = 0.23, p = 0.64; preening: F = 1.47, p = 0.24; short hop: F = 2.01, p = 0.17; calls: F = 0.01, p = 0.91) for any behavior.Based on precedence for a “quiet listening period,” we also measured the time delay from song playback onset to the first, non-look around behavior 2 = 0.19), and showed a positive correlation, opposite to the expected negative correlation.We noted that the MS females had higher overall baseline levels of activity than SS birds prior to song playback onset  = 3.79, p = 0.05, Wilk's λ = 0.66). It was therefore possible that a bird's behavior prior to song onset reliably predicted the delay time, which would suggest that delay times reflect general activity levels or states, not behavioral responses to song playback per se. If so, it would be reasonable to expect that higher behavioral rates would correlate with shorter delay times (i.e. more active birds sit quietly for less time during playbacks). Linear regression of the baseline behavioral measures to delay times, however, failed to find a significant overall relationship  = 2.29; p = 0.08), had low predictive power  = 2.41, p = 0.04, Wilk's λ = 0.72). Therefore, we considered the possibility that rates of activity were different once the birds began to behave after the delay was over. Rate differences might indicate some persistent alteration in behavioral motivation after the delay ended, distinct from simply the number and duration of behaviors we previously analyzed. When we analyzed the rates of each behavior for main effects of Population or Song Type, and their interaction, we detected only one significant difference: the rate of preening was higher in MS compared to SS birds  = 6.29, p = 0.02). There is a similar Population difference in preening in the baseline data  = 6.46, p = 0.02), that disappears in the normalized data  = 1.32, p = 0.26). Further, there is no effect of Song Type  = 0.39, p = 0.53) or a Population*Song Type interaction  = 0.01, p = 0.93) on preening rate, indicating that behavioral rates, including preening, are not altered by song playback.As expected, we found a significant difference between labeling intensity in birds left in silence compared to other birds  = 5.20, p<0.01) using MLd ZENK staining to assay the magnitude of auditory experience. There was no difference in MLd staining between birds that heard a Popular or Unpopular song first  = 2.08, p = 0.17), or between MS and SS birds  = 1.19, p = 0.29). We analyzed three categories of Arc hybridization: cytoplasmic only (Arc induced by first song playback only), nuclear only (Arc induced by second song playback only), cytoplasmic and nuclear double-localized (Arc induced by both songs), in three subregions of auditory forebrain: CMM, dNCM, and vNCM. All measures were significantly lower in Silence birds compared to birds who heard song playbacks ≥2.68, p≤0.03). Further, in the females that experienced song playbacks, there were no differences in any measure between the Popular songs ≤1.61, p≥0.13) or Unpopular songs ≤0.97, p≥0.33) from Song Pairs 1 and 2. We therefore combined data from both Song Pairs to analyze subcellular patterns of Arc label in relation to Population and Song Type. We report results from birds that heard playbacks below.In CMM, there was a significant interaction between Population and Song Type for CMM cytoplasmic  = 8.47, p<0.01) staining, with similar trends in intranuclear  = 3.50, p = 0.06) and double-localized  = 3.84, p = 0.06) staining. The Population* Song Type interaction in cytoplasmic staining is due to fewer Arc labeled cells in the MS birds who heard Popular song first compared to MS birds that heard Unpopular song playbacks first  = 5.32, p = 0.04); i.e. there is lower Arc expression in CMM in response to Popular song playbacks. A similar trend is seen in the MS intranuclear label  = 3.47, p = 0.06). SS birds show no difference in cytoplasmic or intranuclear cell numbers after Popular and Unpopular playbacks  = 0.06, p = 0.81; intranuclear: F = 0.05, p = 0.86) .In NCM, there was a significant interaction between Population and Song Type for dNCM cytoplasmic label  = 4.62, p = 0.03), but not for any of the other measures  = 0.06, p = 0.81; double-localized F(1.51) = 0.68, p = 0.41; 2<0.04, F<1.20, p>0.29).In CMM, dNCM, and vNCM, we counted more cells with cytoplasmic Arc label than intranuclear label . Most ce2<0.003; F<1.064; p>0.31) or with delay durations  = 0.08, p = 0.78; Unpopular: R2 = 0.022, F = 0. = 53, p = 0.47).It was possible that the MS birds were in mate pairs and in an active reproductive state, while SS birds could not be reproducing. As an indirect measure of reproductive status, and therefore circulating hormone levels, we quantified three categories of ovarian follicles Zebra finches form long-term mate pairs and live in complex social communities. Song likely contributes to the establishment and maintenance of social bonds, including those between partners. Adult females distinguish their mate's song from other songs and social context enhances genomic responses to song playback Behaviorally, the time of delay is selectively modulated in the MS birds by acoustic properties in the songs. There are two main possible explanations for these findings. One is that the MS birds have a short delay during Popular song playbacks because they initiate an active response to an “attractive” song. There was, however, no strong evidence for an increased activity level in the MS birds during Popular song playbacks. Another possible explanation is that the delay represents a quiet listening period for auditory processing or learning, and the MS birds need less time for these processes when they hear Popular songs. The delay time was previously described in a paradigm of familiar and novel song playbacks The MS birds also showed a selective, distinctive pattern of Arc induction in the auditory forebrain in response to Popular song playbacks. Generally, Popular song playbacks induced fewer cells to transcribe Arc than Unpopular song playbacks in MS but not SS birds; the interaction was significant in CMM and dNCM, but not vNCM, though Arc induction patterns were similar in all three regions. The effect of Song Type was more pronounced when we analyzed the cytoplasmic label compared to intranuclear and double-localized staining. The difference may reflect a difference in our detection sensitivity, as the trend is similar for both subcellular locations but we counted a lower percentage of labeled cells in the nucleus. A high percentage of cells with intranuclear Arc mRNA also contained cytoplasmic staining, suggesting that both songs activate transcription in a similar subset of cells.Arc is required for long-term memory processes and functions as a structural protein that directs morphological substrates of synaptic strength c.f. As the Mixed Sex housing condition is the normal environment, our results suggest that SS birds lose discrimination between the Popular and Unpopular song on both the neurogenomic and behavioral levels. We considered that age or endocrine status could contribute to these results. All of the birds were adult females of unknown exact ages. However, it is possible, given the logistics of setting up the aviaries, that the SS population was 6–9 months older than the MS birds. Behavioral effects of aging have not been described in these birds, but it is formally possible that base energy levels or auditory discrimination capabilities were lower in the SS birds compared to the MS birds. MS birds did perform more behaviors than SS birds overall but the fact that Unpopular song playbacks elicited the same delay times in MS as SS birds demonstrates that MS birds were capable of sitting quietly for long periods. Further, several lines of evidence described above show that the delay durations were independent of overall activity levels. Although we did not directly test it, we are also not aware of specific reports of a significant age-related decline in auditory processing within adult songbirds.It was also possible that MS and SS females differed in their estradiol levels, affecting auditory processing or behavioral responsiveness Implicit in our discussion is the idea that neurogenomic indicators of song playback processing in the auditory forebrain are directly related to how a bird behaviorally responds. It is possible that Arc induction within subregions of the auditory forebrain reflect processing that informs the neural systems that control the time of delay to an active behavioral response. It is also possible that both the Arc induction and time of delay result from some as-yet-identified third process. Our experimental design permitted us to identify this brain-behavior connection but not to reconcile between mechanistic options.This study does demonstrate that social information embedded within the acoustic structure of song is sufficient to cause selective neurogenomic and behavioral responses, but only in females who are living in normal social environments. Our stimulus songs overlapped in acoustic features, thus it is still unclear what components of the song structure might provide the signals that induce distinct brain and behavioral responses. These results, however, strengthen the connections between natural experience, neurogenomic regulation, and behavioral response.Table S1Popular and Unpopular acoustic traits.(PDF)Click here for additional data file.


Approximately 10% patients who undergo non-cardiac surgery show biochemical evidence of myocardial injury, which is associated with cardiac complications and death.[The aim of this study was to determine whether or not intraoperative tachycardia is associated with postoperative myocardial injury.This was a post-hoc analysis of an international observational cohort study of patients undergoing non-cardiac surgery. Maximum 1,197 patients (7.9%) of 15,792 patients showed evidence of myocardial injury and 315 (2.0%) died. Maximum intraoperative heart rate was associated with myocardial injury and mortality. Minimum intraoperative heart rate was negatively associated with myocardial injury, but not mortality (figure Intraoperative tachycardia was associated with adverse postoperative outcomes. Further work is required to refine the relation between perioperative heart rate and post-operative clinical outcomes and whether or not heart rate modulating drugs reduce perioperative myocardial injury.TA is supported by an MRC/BJA Clinical Research Training Fellowship.


Critical Care, Ostermann and colleagues reported that myocardial infarction (MI), screened by plasma troponin and electrocardiography changes, is common and often clinically unrecognized in the ICU. Although the clinical significance of underdiagnosed MIs remains unclear, this approach may help to target and further investigate the at-risk population for appropriate therapy.In ICU settings, the diagnosis and treatment of acute myocardial infarction (AMI) are challenging, partly because cardiac troponin increase occurs frequently. In the previous issue of  Critical Care, Ostermann and colleagues [In the previous issue of lleagues  studied lleagues  - has liP = 0.02).Intensivists frequently rely on electrocardiography (ECG) evidence of myocardial ischemia, but continuous 2- or 12-lead ECG routine screening remains poorly satisfactory because of a low sensitivity and lack of specificity compared with non-ICU patients ,4. It maThese findings confirm previous reports underlining that MI, routinely screened by combined ECG changes and plasma hs-cTnT, is quite common and underdiagnosed in ICUs . It is, ICU patients are at high risk for myocardial ischemia because of older age, increased intrinsic and extrinsic sympathetic stimulation, hypoxia, vasopressor use, and coagulation disorders. However, myocardial necrosis may be induced by coronary atherothrombosis or by other triggers that cause an imbalance between coronary oxygen supply and myocardial oxygen demand . The preThus, several issues regarding the use of hs-cTn in the ICU should be addressed. First, determination of the 99th percentile of hs-cTn could be either variable in this specific population mostly characterized by older age and comorbidities. While this value increases in older (more than 65 years old) patients admitted to the emergency room , it dramIn conclusion, the diagnosis of AMI remains challenging in the ICU, and the use of high-sensitivity troponin T as a diagnostic tool should be prudent because it may lead to an overestimation of evidence of ischemia. To increase the accuracy for diagnosing MI, one should reserve invasive or non-invasive procedures, such as bedside echocardiography or coronary angiography, to a targeted population. The work of Ostermann and colleagues  providesAMI: Acute myocardial infarction; cTn: Cardiac troponin; cTnT: Cardiac troponin T; ECG: Electrocardiography; hs-cTn: High-sensitivity cardiac troponin; hs-cTnT: High-sensitivity cardiac troponin T; MI: Myocardial infarction.The authors declare that they have no competing interests.All authors read and approved the final manuscript.