The aim of this study was to evaluate sympathetic responses to experimentally induced periodic breathing/Cheyne-Stokes respiration (PB/CSR)-like patterns in optimally treated patients with chronic heart failure (CHF) compared with matched healthy controls. Muscle sympathetic nerve activity (MSNA) was recorded in 22 patients with systolic CHF (63 ± 9 years; left ventricular ejection fraction 31 ± 8

BACKGROUND:Transthoracic echocardiography is recommended for the initial evaluation of patients with suspected pulmonary hypertension (PH), while right heart catheterization (RHC) is indicated to measure mean pulmonary artery pressure (mPAP). Although different echocardiographic algorithms have been proposed to estimate mPAP, these are based on limited validation, often in small or selected populations, and all predate the revised PH diagnostic threshold (mPAP >20 mm Hg). This study aimed to evaluate and compare the diagnostic performance of 5 echocardiographic formulas for estimating mPAP in a large cohort of patients referred to RHC. METHODS:Consecutive patients undergoing clinically indicated RHC and transthoracic echocardiograph within 7 days were prospectively enrolled from a PH referral center over a 10-year period. Echocardiographic mPAP estimates were calculated using 5 previously proposed formulas derived from tricuspid regurgitation (TR), pulmonary regurgitation (PR), and pulmonary flow acceleration time. Diagnostic accuracy was assessed through correlation analysis, Bland-Altman plots, and receiver operating characteristic curves, applying the updated PH definition (mPAP >20 mm Hg). RESULTS:Out of 571 patients included (age 68 ± 13 years, 50% male), 450 (79%) were diagnosed with PH. All echocardiographic formulas showed significant correlation with invasive mPAP (P < .001). The formula based on minimal end-diastolic PR pressure showed the best correlation (mPAPDPmin; R = 0.92) and diagnostic accuracy (area under the curve, 0.96 [0.95-0.98]), outperforming mPAP derived from TR velocity (area under the curve, 0.91 [0.89-0.93]) and other formulas (all P < .001). The mPAPDPmin value also showed minimal bias (+1.21 mm Hg) with narrow limits of agreement (-7.14 to +9.56 mm Hg) and high accuracy at the fixed 20 mm Hg threshold (sensitivity, 99%; specificity, 82%). CONCLUSIONS:Echocardiographic estimation of mPAP using the mPAPDPmin formula provides excellent diagnostic accuracy for PH, outperforming other established echocardiographic algorithms.

Abstract Background The diagnosis of pulmonary hypertension (PH) relies on measuring pulmonary artery pressures at right heart catheterization (RHC). Echocardiographic tricuspid regurgitation velocity (TRV) is a screening tool to define PH probability. While latest guidelines reduced RHC threshold for PH diagnosis, TRV thresholds were not. We aimed to update TRV thresholds for PH probability according to the novel RHC criteria. Methods Patients undergoing RHC for suspected PH were prospectively enrolled. A retrospective cohort was used for external validation. All patients underwent echocardiography and RHC within 6-hours under stable conditions. Results In the derivation cohort (n=400), 85% of patients had PH at RHC. However, only 68% had intermediate or high PH probability with the conventional 280 cm/s TRV threshold (76% sensitivity, 24% false-negative rate). The optimal threshold for low probability was 250 cm/s, with higher sensitivity (90%, 10% false-negative rate). In the validation cohort (n=1,348), 76% of patients had PH. In this cohort, the proposed 250 cm/s low probability threshold was confirmed to hold high sensitivity (97%, 3% false-negative rate). Conclusions This large multicenter derivation-validation study supports lowering the TRV threshold from ≤280 to ≤250 cm/s to decrease false-negative rate and missing referral to RHC in patients with suspected PH. Graphical abstract

Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure (mPAP) ›20 mmHg at rest, as assessed by right heart catheterization (RHC). Echocardiography often serves as the first–line diagnostic examination for patients with suspected PH. However, no echocardiographic estimate of mPAP is currently recommended by guidelines, as the various formulas proposed to date lack large–scale diagnostic and prognostic validation. The aim of this study was to evaluate the diagnostic performance of different formulas for assessing mPAP through echocardiography in a large cohort of patients undergoing RHC for suspected PH. This study included 419 patients (216 men, aged 69±12 years) undergoing RHC for suspected PH. At RHC, mPAP was 28±8 mmHg, and according to the 2022 European Society of Cardiology guidelines, 313 patients (74.5%) were diagnosed with PH: 137 (33%) pre–capillary, 99 (24%) post–capillary, 95 (26%) combined, and 18 (4%) unclassified. Echocardiography was performed within 1.8±2.2 days of RHC and mPAP was estimated through four different formulas where applicable: 1)mPAPsPAP= 0.61*sPAP+2, where sPAP is systolic pulmonary arterial pressure (available in 419 patients [100%], mean value 32±9 mmHg); 2)mPAPAT= 80−(0.5*RVOT–AT), where RVOT–AT is the acceleration time of blood flow through right ventricular outflow tract (available in 351 patients [83%], mean value 32±16 mmHg); 3)mPAPPRmax= 4*(PRmax)2+RAP, where PRmax is the early–diastolic flow velocity of pulmonary regurgitation and RAP is the echocardiography estimate of right atrial pressure (available in 206 patients [49%], mean value 30±13 mmHg); 4)mPAPPRmin= 2/3*dPAP+1/3*sPAP, where dPAP= 4*(PRmin)2+RAP and PRmin is the end–diastolic flow velocity of pulmonary regurgitation (available in 419 patients [100%], mean value 28±8 mmHg). Each measure was correlated with invasive mPAP (ρ=0.86 for mPAPsPAP; ρ=0.28 for mPAPAT; ρ=0.70 for mPAPPRmax; ρ=0.93 for mPAPPRmin; all p‹0.001). At receiver–operating characteristic (ROC) curve analysis (Figure 1), mPAPPRmin exhibited a substantially higher area under the curve (AUC 0.95, 95%CI 0.93–0.98) in identifying patients with PH compared to mPAPsPAP (AUC 0.87, 95%CI 0.81–0.92), mPAPPRmax (AUC 0.81, 95%CI 0.75–0.88) and mPAPAT (AUC 0.61, 95%CI 0.52–0.70). The echocardiographic estimate of mPAP, particularly when derived using the mPAPPRminformula, is feasible and highly accurate for diagnosing PH.

Background Tricuspid annular plane systolic excursion (TAPSE), Doppler tissue imaging–derived tricuspid lateral annular systolic wave velocity (S′), and right ventricular fractional area change (RV‐FAC) are the most widely used echocardiographic measures of right ventricular systolic function. This study aimed to compare the prognostic value of TAPSE, S′, and RV‐FAC in a large cohort of patients with chronic heart failure. Methods Consecutive outpatients with heart failure and left ventricular ejection fraction <50% on guideline‐recommended therapies undergoing echocardiography were followed up for the end point of cardiac and all‐cause death. Results Among 1590 patients (71±12 years, 77% men, left ventricular ejection fraction 34%±9%), 202 (13%) died from cardiac causes during a median follow‐up of 28 (interquartile range, 14–40) months. According to the recommended cut points for TAPSE (<17 mm), S′ (<9.5 cm/s), or RV‐FAC (<35%), right ventricular systolic dysfunction was found in 37%, 40%, and 35% of patients, respectively, with 21%, 31%, and 33% of discordant cases comparing TAPSE versus S′, TAPSE versus RV‐FAC, and S′ versus RV‐FAC. Both TAPSE <17 mm and RV‐FAC <35% were more accurate than S′ <9.5 cm/s in predicting the risk of cardiac death (P<0.001), and their combination showed incremental prognostic power (P<0.001). Adding S′ to the combination of TAPSE and RV‐FAC did not provide further incremental value (P=0.145). Similar findings were obtained when all‐cause death was considered as the end point. Conclusions In patients with chronic heart failure and left ventricular ejection fraction <50%, TAPSE, and RV‐FAC are more accurate than S′ in predicting the risk of cardiac and all‐cause death. Considering both RV‐FAC and TAPSE provides incremental prognostic value.

BACKGROUND:An echocardiographic algorithm to estimate pulmonary capillary wedge pressure (ePCWP) and pulmonary vascular resistance (ePVR) has been recently validated versus right heart catheterization. OBJECTIVE:To assess the prognostic significance of these measures in heart failure (HF) patients with reduced and mildly reduced ejection fraction. METHODS:Consecutive outpatients with HF and left ventricular ejection fraction (LVEF) <50% undergoing echocardiography were selected and followed up for the composite end point of all-cause death or HF hospitalization. RESULTS:Out of 2,214 patients (71 ± 12 years, 76% males, LVEF 35% ± 9%), ePCWP (16 ± 6 mm Hg) was elevated (>15 mm Hg) in 52% of cases and ePVR (1.7 ± 0.7 Wood units) was elevated (>2 Wood units) in 25% of cases. Patients with increased ePCWP were older and had a higher New York Heart Association class, more pronounced cardiac remodeling, systolic/diastolic dysfunction, and neurohormonal activation, particularly when ePVR was also elevated (P < .001). Over a median follow-up of 33 (17-48) months, both measures stratified patients for the risk of the primary end point (log-rank 151 for ePCWP and 60 for ePVR; P < .001). At adjusted regression analysis, ePCWP (hazard ratio for 1 mm Hg increase 1.03 [95% CI, 1.01-1.04]; P < .001) but not ePVR (P = .07) predicted the primary end point, even in patients with atrial fibrillation (P = .019), outperforming current diastolic dysfunction grading (P < .001) and both E/e' and left atrial volume index (P < .001). The addition of ePCWP to a multivariable prognostic model improved the accuracy of risk prediction (P < .001). CONCLUSION:The echocardiographic estimates of PCWP retained clinical and prognostic significance in a large contemporary cohort of patients with chronic HF and LVEF <50%.

Abstract Background An echocardiographic algorithm to estimate pulmonary capillary wedge pressure (ePCWP) and pulmonary vascular resistance (ePVR) has been recently validated versus right heart catheterization (1). Purpose The aim of this study was to assess the prognostic significance of these measures in heart failure (HF) patients. Methods Consecutive outpatients with HF and left ventricular ejection fraction (LVEF) <50% undergoing echocardiography were selected and followed-up for the composite endpoint of cardiac death or HF hospitalization. Results Out of 2,214 patients (71±12 years, 76% males, LVEF 35±9%), ePCWP (16±6 mmHg) was elevated (>15 mmHg) in 52% of cases and ePVR (1.7±0.7 WU) was elevated (>2 WU) in 25% of cases. Patients with increased ePCWP were older, had a higher NYHA class, more pronounced cardiac remodeling, systo/diastolic dysfunction, and neurohormonal activation, particularly when ePVR was also elevated (p<0.001). Over a median follow-up of 33 (17-48) months, both measures stratified patients for the risk of the primary endpoint (Log-Rank 152 for PCWP, and 44 for ePVR, p<0.001). At adjusted regression analysis, ePCWP (hazard ratio for 1 mmHg increase 1.03 [95%CI 1-01-1-05], p<0.001) but not ePVR (p=0.584) predicted the primary endpoint, even in the subpopulation of patients with atrial fibrillation (p=0.003). ePCWP outperformed current diastolic dysfunction grading (Δ C-statistics 0.068 [95% CI 0.045-0.093], p<0.001), and stratified patients’ risk across each diastolic dysfunction grade at univariate analysis (Grade I: p=0.002; Grade II-III: p<0.001; Indeterminate cases: p=0.010). The addition of ePCWP to a multivariable prognostic model, including patients’ age, NYHA class III-IV, chronic obstructive pulmonary disease, estimated glomerular filtration rate, NT-proBNP, and LVEF, improved the accuracy of risk prediction (Δ C-statistics 0.008 [95% CI 0.002-0.014], p=0.007). Conclusion The echocardiographic estimates of PCWP retained clinical and prognostic significance in a large contemporary cohort of patients with chronic HF and LVEF <50%. This algorithm could facilitate early identification of high-risk patients, possibly reducing the need of right heart catheterisation, and allowing a tailored therapeutic approach. Graphical abstract KM curves for the primary endpoint - AF

Objective: Renal denervation (RDN) attenuates the sympathetic nervous system overactivity that characterizes patients with elevated blood pressure (BP). Given that accurate predictors of BP response to RDN remain to be identified and that metaiodobenzylguanidine (MIBG) scintigraphy allows non-invasive assessment of sympathetic nerve activity, we explored if the kidney, heart and lung MIBG uptake predict BP response to RDN. Design and method: Thirteen patients with difficult-to-treat hypertension underwent radiofrequency-based RDN. Before the procedure, clinical and pharmacological history, office and ambulatory BP values and cardiovascular risk factors were recorded. Patients also underwent preprocedural rest echocardiography and MIBG scintigraphy. After RDN, a follow-up visit was performed at 3 months, with registration of office and ambulatory BP values. We considered as responders (R) those patients showing a reduction of office BP values on unchanged BP-lowering treatment and those who reduced the number and/or dosage of BP-lowering medications while maintaining optimal control of office BP. Results: Seven patients were classified as R (1 woman, mean age 48±11 years), while 6 were non-responders (NR) (2 women, mean age 50±8 years). The reduction in office systolic and diastolic BP values from baseline to 3 months was significantly larger in R vs NR (p=0.01). Furthermore, the burden of BP-lowering medications after the procedure was reduced more significantly in R (-44%) than NR (-16%), p<0.01. Baseline heart rate was the only clinical parameter significantly different between R (median 82, IQR [67-98]) bpm vs NR (median 62, IQR [60-72]) bpm, p<0.05. In early MIBG acquisitions, the lung/mediastinum ratio on both sides showed higher MIBG uptake in R vs NR (p<0.05). In late acquisitions, only the left side showed a significant difference between R and NR (p<0.05). There was a higher MIBG uptake in the right vs. left lung in the whole population and in R vs NR. All other MIBG scintigraphy parameters were similar between groups. Conclusions: Among patients with difficult-to-treat hypertension, those responding to RDN showed a higher lung/mediastinum ratio at MIBG scintigraphy and a higher heart rate before the procedure. Further studies are needed to confirm these preliminary results.

Background and Aims Though widely used to classify heart failure (HF) patients, the prognostic role of left ventricular ejection fraction (LVEF) is debated. We hypothesized that the echocardiographic measures of forward LV output, being more representative of cardiac hemodynamics, may improve risk prediction in a large cohort of HF patients with systolic dysfunction. Methods Consecutive stable HF patients with LVEF <50% on guideline-recommended therapies undergoing an echocardiography including the evaluation of forward LV output (i.e., LV outflow tract velocity-time integral [LVOT-VTI], stroke volume index [SVi], and cardiac index [CI]) over a 6-year period, were selected and followed-up for the endpoint of cardiac and all-cause death. Results Among the 1,509 patients analyzed (71±12 years, 75% males, LVEF 35±9%), 328 (22%) died during a median 28-month (14-40) follow-up, 165 (11%) of which for cardiac causes. At multivariable regression analysis, LVOT-VTI (<0.001), SVi (p<0.001), and CI (p<0.001), but not LVEF (p>0.05), predicted cardiac and all-cause death. The optimal prognostic cut-offs for LVOT-VTI, SVi, and CI were 15 cm, 38 mL/m2, and 2 L/min/m2, respectively. Adding each of these measures to a multivariable risk model (including clinical, biohumoral, and echocardiographic markers) improved risk prediction (p<0.001). Among the different measures of forward LV output, CI was less accurate than LVOT-VTI and SVi. Conclusion The echocardiographic evaluation of forward LV output improves risk prediction in HF patients across a wide LVEF spectrum over other well-established clinical, biohumoral, and echocardiographic prognostic markers.

Microelectrode recordings from human peripheral and cranial nerves provide a means to study both afferent and efferent axonal signals at different levels of detail, from multi- to single-unit activity. Their analysis can lead to advancements both in diagnostic and in the understanding of the genesis of neural disorders. However, most of the existing computational toolboxes for the analysis of microneurographic recordings are limited in scope or not open-source. Additionally, conventional burst-based metrics are not suited to analyze pathological conditions and are highly sensitive to distance of the microelectrode tip from the active axons. To address these challenges, we developed an open-source toolbox that offers advanced analysis capabilities for studying neuronal reflexes and physiological responses to peripheral nerve activity. Our toolbox leverages the observation of temporal sequences of action potentials within inherently cyclic signals, introducing innovative methods and indices to enhance analysis accuracy. Importantly, we have designed our computational toolbox to be accessible to novices in biomedical signal processing. This may include researchers and professionals in healthcare domains, such as clinical medicine, life sciences, and related fields. By prioritizing user-friendliness, our software application serves as a valuable resource for the scientific community, allowing to extract advanced metrics of neural activity in short time and evaluate their impact on other physiological variables in a consistent and standardized manner, with the final aim to widen the use of microneurography among researchers and clinicians.

BACKGROUND: Risk scores are important tools for the prognostic stratification of pulmonary arterial hyper-tension (PAH). Their performance and the additional impact of comorbidities across age groups is unknown.METHODS: Patients with PAH enrolled from 2001 to 2021 were divided in & GE;65 years old vs <65 years old patients. Study outcome was 5-year all-cause mortality. French Pulmonary Hypertension Network (FPHN), FPHN noninvasive, Comparative, Prospective Registry of Newly Initiated Therapies for Pul-monary Hypertension (COMPERA) and Registry to Evaluate Early and Long-term PAH Disease Man-agement (REVEAL 2.0) risk scores were calculated and patients categorized at low, intermediate and high risk. Number of comorbidities was calculated.RESULTS: Among 383 patients, 152 (40%) were & GE;65 years old. They had more comorbidities (number of comorbidities 2, IQR 1-3, vs 1, IQR 0-2 in <65 years patients). Five-year survival was 63% in & GE;65 vs 90% in <65 years. Risk scores correctly discriminated the different classes of risk in the overall cohort and in the older and younger groups. REVEAL 2.0 showed the best accuracy in the total cohort (C-index 0.74, standard error -SE-0.03) and older (C-index 0.69, SE 0.03) patients, whereas COM-PERA 2.0 performed better in younger patients (C-index 0.75, SE 0.08). Number of comorbidities was associated with higher 5-year mortality, and consistently increased the accuracy of risk scores, in youn-ger but not in older patients. CONCLUSIONS: Risk scores have similar accuracy in the prognostic stratification of older vs younger PAH patients. REVEAL 2.0 had the best performance in older patients and COMPERA 2.0 had it in younger patients. Comorbidities increased the accuracy of risk scores only in younger patients. J Heart Lung Transplant 2023;42:1082-1092 & COPY; 2023 International Society for Heart and Lung Transplantation. All rights reserved.

The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases.

Le apnee centrali (central apneas, CA) e il respiro periodico (periodic breathing, PB) sono i più comuni disturbi respiratori nello scompenso cardiaco, interessando circa il 50% dei pazienti. Una volta considerati fenomeni correlati al sonno, le CA e il PB possono verificarsi anche nel periodo diurno e la loro presenza durante la veglia anche in posizione ortostatica e durante lo sforzo è stata associata ad un aggravamento clinico e prognostico. L’attivazione del chemoriflesso, il ritardo del tempo di circolo e l’alterazione del plant gain sono i determinanti fisiopatologici delle CA. Sebbene l’implementazione della terapia medica ottimale per lo scompenso cardiaco rappresenti il primo passo nella gestione delle CA, finora, nessuna terapia specifica ha dimostrato di diminuirne il relativo impatto prognostico. In particolare, l’uso della ventilazione non invasiva ha apportato risultati contraddittori nel contesto di ampi studi clinici randomizzati. Disegnare e testare terapie mirate ai determinanti fisiopatologici della CA, come la sensibilità chemocettiva, potrebbe rivelarsi utile nel prossimo futuro.

Objective: Renal denervation (RDN) is increasingly used to reduce sympathetic outflow and improve blood pressure (BP) control in patients with resistant or difficult-to-treat arterial hypertension. However, the BP response to the procedure is variable, and factors influencing this variability remain largely unknown. Sympathetic outflow recorded before the procedure might predict the BP response to RDN, although results from different studies remain conflicting. These discrepancies might depend on the limited characterization of the sympathetic outflow before RDN, making its better definition an important goal to refine the patient selection. Design and method: We prospectively enrolled patients with difficult-to-treat arterial hypertension undergoing RDN. Patients underwent an extensive clinical evaluation, and the muscle sympathetic nerve activity (MSNA) in resting conditions and during respiratory maneuvers (controlled inspiratory apneas, evaluation of chemoreflex sensitivity to hypoxia and hypercapnia with the rebreathing technique) was recorded through microneurography. Sympathetic burst frequency, incidence, amplitude, duration and integral, as well as inter-burst interval, were calculated with a semi-automated in-house software. Results: Table 1 reports the clinical characteristics of the 10 patients that were enrolled and underwent MSNA recording before RDN. Only in 6 patients the MSNA signal was clearly interpretable and, of these, 5 subjects (Figure 1) completed the whole battery of the respiratory stimuli (2 patients couldn’t perform chemoreflex testing due to panic attack and loss of neural signal). Apnea increased the burst frequency and incidence in all patients, although the magnitude of the changes from the resting acquisition was variable. The MSNA responses to the other respiratory maneuvers were jeopardized. Burst duration remained stable, whereas an increased MSNA could be observed (subjects 1 and 3) in terms of risen burst integral and reduced inter-burst interval compared to baseline. The sympathetic response to inspiratory apneas seems mediated by chemoreflex responses in these patients. The other subjects did not show such variations. Conclusions: Respiratory maneuvers are feasible during MSNA acquisitions and unveil different patterns of sympathetic responses in patients with hypertension undergoing RDN. Such differences might be missed at rest but could represent novel predictors of the BP response to the procedure.

AIMS:Left ventricular outflow velocity-time integral (LVOT-VTI) has been shown to improve outcome prediction in different patients' subsets, with or without heart failure (HF). Nevertheless, the prognostic value of LVOT-VTI in patients with HF and secondary mitral regurgitation (MR) has never been investigated so far. Therefore, in the present study, we aimed to assess the prognostic value different metrics of LV forward output, including LVOT-VTI, in HF patients with secondary MR. METHODS AND RESULTS:Consecutive patients with HF and moderate-to-severe/severe secondary MR and systolic dysfunction (i.e., left ventricular ejection fraction [LVEF] <50%) were retrospectively selected and followed-up for the primary endpoint of cardiac death. Out of the 287 patients analyzed (aged 74 ± 11 years, 70% men, 46% ischemic etiology, mean LVEF 30 ± 9%, mean LVOT-VTI 20 ± 5 cm), 71 met the primary endpoint over a 33-month median follow-up (16-47 months). Patients with an LVOT-VTI ≤17 cm (n = 96, 32%) showed the greatest risk of cardiac death (Log Rank 44.3, p < 0.001) and all-cause mortality (Log rank 8.6, p = 0.003). At multivariable regression analysis, all the measures of LV forward volume (namely LVOT-VTI, stroke volume index, cardiac output, and cardiac index) were predictors of poor outcomes. Among these, LVOT-VTI was the most accurate in risk prediction (univariable C-statistics 0.70 [95%CI 0.64-0.77]). CONCLUSION:Left ventricular forward output, noninvasively estimated through LVOT-VTI, improves outcome prediction in HF patients with low LVEF and secondary MR.

Central apneas (CA) and periodic breathing (PB) are the most common related breathing disorders in heart failure, being observed in up to 50% of patients. Once considered only a sleep-related phenomenon, actually CA/PB occur across the whole 24 h period and their presence in the awake patient even in the upright position and during physical effort has been associated with a worse clinical profile and a greater mortality. Chemoreflex activation, circulatory time delay and altered plant gain are the pathophysiological determinants. While the use of guideline-recommended medical and device treatment represents the first step in the management of CA in heart failure patients, no specific therapy has been demonstrated to reduce CA-related impact on mortality. In particular, the use of non-invasive ventilation has yielded contradictory results in the context of large-scale randomized clinical trials. The design and testing of therapies targeting the pathophysiological triggers of CA, such as chemoreflex sensitivity, may prove valuable in the next future.