Single-shot measurement of longitudinal phase space beam profile in an electron storage ring.

A novel scheme to measure the longitudinal emittance and phase space profile in an electron storage ring by using correlations between time and the vertical coordinate, and between energy and the horizontal coordinate, is proposed. This longitudinal profile measurement scheme will help to demonstrate recent results of advanced studies for manipulating the longitudinal beam profile and for investigating beam instability in an electron storage ring.

Investigation of the damping wiggler effect and application on the PAL fourth-generation storage ring.

An investigation of the damping wiggler effect to reduce the emittance in the Pohang Accelerator Laboratory (PAL), a fourth-generation storage ring (4GSR) that uses a multi-bend achromat, is presented. A 4GSR lattice which has reduced emittance and increased dynamic aperture to amplify the synergy with two existing light sources (PLS-II and PAL-XFEL) at PAL is described.

Error rate of automated calculation for wound surface area using a digital photography.

BACKGROUND: Although measuring would size using digital photography is a quick and simple method to evaluate the skin wound, the possible compatibility of it has not been fully validated. PURPOSE: To investigate the error rate of our newly developed wound surface area calculation using digital photography. METHODS: Using a smartphone and a digital single lens reflex (DSLR) camera, four photographs of various sized wounds (diameter: 0.5-3.5 cm) were taken from the facial skin model in company with color patches. The quantitative values of wound areas were automatically calculated. The relative error (RE) of this method with regard to wound sizes and types of camera was analyzed. RESULTS: RE of individual calculated area was from 0.0329% (DSLR, diameter 1.0 cm) to 23.7166% (smartphone, diameter 2.0 cm). In spite of the correction of lens curvature, smartphone has significantly higher error rate than DSLR camera (3.9431±2.9772 vs 8.1303±4.8236). However, in cases of wound diameter below than 3 cm, REs of average values of four photographs were below than 5%. In addition, there was no difference in the average value of wound area taken by smartphone and DSLR camera in those cases. CONCLUSION: For the follow-up of small skin defect (diameter: <3 cm), our newly developed automated wound area calculation method is able to be applied to the plenty of photographs, and the average values of them are a relatively useful index of wound healing with acceptable error rate.

Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain.

Survival and proliferation of cancer cells are often associated with hyperactivity of the serine/threonine kinase, Akt. Herein, we show that prosurvival activity of Akt can be converted into prodeath activity by embedding an Akt recognition sequence in the apoptogenic BH3 domain of human BIM. The recognition sequence was created by introducing two mutations, I155R and E158S, into the core region of the BIM BH3 domain. Although a 21-mer BIM BH3 peptide containing these two mutations bound weakly to BCL-XL and BCL-2, this peptide with phosphorylation of Ser158 bound to these proteins with a dissociation constant of <10 nM. The crystal structure of the phosphorylated peptide bound to BCL-XL revealed that the phospho-Ser158 makes favorable interactions with two BCL-XL residues, which cannot be formed with unphosphorylated Ser158. Remarkably, the designed peptide showed a cytotoxic effect on PTEN-null PC3 tumor cells whose Akt activity is aberrantly high. The cell-killing activity disappeared when the cellular Akt activity was lowered by ectopic PTEN expression. Thus, these results lay a foundation for developing a peptide or protein agent that is dormant in normal cells but is transformed into a potent apoptogenic molecule upon phosphorylation by hyperactivity of Akt in cancer cells.

Comparison of negative pressure wound therapy and secondary intention healing after excision of acral lentiginous melanoma on the foot.

BACKGROUND: Melanoma in dark-skinned individuals often develops in an acral lentiginous fashion on the foot and wide excision usually results in a substantial defect. Various repair methods, including free flap, full-thickness skin graft and secondary intention healing (SIH), are used to repair these defects. Recently, use of negative pressure wound treatment (NPWT) has been shown to accelerate wound healing in different types of wound. OBJECTIVES: To compare the functional and cosmetic results of NPWT and SIH in patients who underwent wide excision of melanomas on the foot. METHODS: The wound defects of 22 patients after wide excision of melanoma on the foot were treated using SIH (n = 13) or NPWT (n = 9). RESULTS: There was no significant difference in time to complete wound healing between the two groups. However, evaluation using the Vancouver Burn Scar Assessment Scale at the time of complete healing showed that the mean score of the NPWT group was significantly lower than that of the SIH group. The NPWT group also had significantly better results than the SIH group in terms of total score, vascularity and height of the scars. As for complications, no wound infection was encountered in the NPWT group, whereas eight of the 13 patients in SIH group had wound infections during the course of treatment despite frequent and meticulous aseptic dressing changes. CONCLUSIONS: These results show that, despite the drawback of rather prolonged healing time, NPWT is an excellent therapeutic option for wounds after wide excision of melanoma on the foot, with acceptable functional and cosmetic outcomes.

Different pattern of carotid and myocardial changes according to left ventricular geometry in hypertensive patients.

The relation between left ventricular (LV) hypertrophy and LV function is well known. However, less is known about the vascular changes influenced by LV geometry. We sought to investigate the relationship of LV geometry to carotid arterial and LV function. A total of 476 hypertensive patients were prospectively recruited. All subjects underwent echocardiography and carotid ultrasound. LV geometry is categorized into four groups according to relative wall thickness (RWT) and LV mass index (LVMI). Concentric LV geometry was associated with increased carotid intima-media thickness (IMT), ß-stiffness, and lower strain. All of the carotid parameters showed a stepwise change according to RWT of LV, whereas LV function was worse in hypertrophic geometry, as reflected by significantly lower systolic mitral annular velocity, higher left atrial volume index and E/E' ratio (P<0.001). By multivariate analysis after adjustment for clinical and laboratory parameters, IMT was independently associated with RWT, whereas myocardial function was independently associated with LVMI. Carotid arterial function and IMT showed worse values in concentric geometry, whereas LV systolic and diastolic function were worse in hypertrophic geometry, suggesting a discrepancy between carotid arterial and LV function in hypertensive patients.

First neutral beam injection experiments on KSTAR tokamak.

The first neutral beam (NB) injection system of the Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak was partially completed in 2010 with only 1∕3 of its full design capability, and NB heating experiments were carried out during the 2010 KSTAR operation campaign. The ion source is composed of a JAEA bucket plasma generator and a KAERI large multi-aperture accelerator assembly, which is designed to deliver a 1.5 MW, NB power of deuterium at 95 keV. Before the beam injection experiments, discharge, and beam extraction characteristics of the ion source were investigated. The ion source has good beam optics in a broad range of beam perveance. The optimum perveance is 1.1-1.3 µP, and the minimum beam divergence angle measured by the Doppler shift spectroscopy is 0.8°. The ion species ratio is D(+):D(2)(+):D(3)(+) = 75:20:5 at beam current density of 85 mA/cm(2). The arc efficiency is more than 1.0 A∕kW. In the 2010 KSTAR campaign, a deuterium NB power of 0.7-1.5 MW was successfully injected into the KSTAR plasma with a beam energy of 70-90 keV. L-H transitions were observed within a wide range of beam powers relative to a threshold value. The edge pedestal formation in the T(i) and T(e) profiles was verified through CES and electron cyclotron emission diagnostics. In every deuterium NB injection, a burst of D-D neutrons was recorded, and increases in the ion temperature and plasma stored energy were found.

Development of a plasma generator for a long pulse ion source for neutral beam injectors.

A plasma generator for a long pulse H(+)/D(+) ion source has been developed. The plasma generator was designed to produce 65 A H(+)/D(+) beams at an energy of 120 keV from an ion extraction area of 12 cm in width and 45 cm in length. Configuration of the plasma generator is a multi-cusp bucket type with SmCo permanent magnets. Dimension of a plasma chamber is 25 cm in width, 59 cm in length, and 32.5 cm in depth. The plasma generator was designed and fabricated at Japan Atomic Energy Agency. Source plasma generation and beam extraction tests for hydrogen coupling with an accelerator of the KSTAR ion source have been performed at the KSTAR neutral beam test stand under the agreement of Japan-Korea collaborative experiment. Spatial uniformity of the source plasma at the extraction region was measured using Langmuir probes and ±7% of the deviation from an averaged ion saturation current density was obtained. A long pulse test of the plasma generation up to 200 s with an arc discharge power of 70 kW has been successfully demonstrated. The arc discharge power satisfies the requirement of the beam production for the KSTAR NBI. A 70 keV, 41 A, 5 s hydrogen ion beam has been extracted with a high arc efficiency of 0.9 -1.1 A/kW at a beam extraction experiment. A deuteron yield of 77% was measured even at a low beam current density of 73 mA/cm(2).

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis.

The anti-apoptotic Bcl-2 protein, which confers oncogenic transformation and drug resistance in most human cancers, including breast cancer, has recently been shown to effectively counteract autophagy by directly targeting Beclin1, an essential autophagy mediator and tumor suppressor. However, it remains unknown whether autophagy inhibition contributes to Bcl-2-mediated oncogenesis. Here, by using a loss-of-function mutagenesis study, we show that Bcl-2-mediated antagonism of autophagy has a critical role in enhancing the tumorigenic properties of MCF7 breast cancer cells independent of its anti-apoptosis activity. A Bcl-2 mutant defective in apoptosis inhibition but competent for autophagy suppression promotes MCF7 breast cancer cell growth in vitro and in vivo as efficiently as wild-type Bcl-2. The growth-promoting activity of this Bcl-2 mutant is strongly correlated with its suppression of Beclin1-dependent autophagy, leading to sustained p62 expression and increased DNA damage in xenograft tumors, which may directly contribute to tumorigenesis. Thus, the anti-autophagic property of Bcl-2 is a key feature of Bcl-2-mediated oncogenesis and may in some contexts, serve as an attractive target for breast and other cancer therapies.

Left atrial remodelling in patients with successful percutaneous mitral valvuloplasty: determinants and impact on long-term clinical outcome.

BACKGROUND: Left atrial (LA) volume is an independent prognosticator in various cardiac diseases. The authors assessed the changes of LA volume after successful percutaneous mitral valvuloplasty (PMV) and the impact of LA enlargement on long-term clinical outcome after PMV. METHODS AND RESULTS: From a prospective PMV registry started in 1988, 303 patients (242 women, age: 39.3+/-10.8 years) who had undergone successful PMV were followed for 4-20 years (median 11 years). Echocardiographic examination including LA volume measurement was performed before PMV and repeated after PMV. LA volume decreased from 92+/-50 to 69+/-42 ml (p < 0.001) immediately after PMV and remained stationary until 1 year after PMV. Since then, LA volume subsequently increased exceeding the pre-PMV level by 8 years after PMV. Multivariate analysis showed that LA volume increase at 10 years after PMV was independently related to the post-PMV mitral valve area, the echo score, the presence of atrial fibrillation and post-PMV LA volume. On multiple regression analysis, pre-PMV LA volume and percentage change of LA volume immediately after PMV emerged as independent predictors of event-free survival along with age, pre-PMV tricuspid regurgitation and post-PMV mitral valve area. Ten-year survival rate was 93% in patients with smaller LA before PMV (< or =72 ml/m(2)), whereas it was only 60% in those with larger LA (>72 ml/m(2)). CONCLUSIONS: Progressive increase of LA volume was observed even after successful PMV. Larger pre-PMV LA volume was associated with poor prognosis.

Left ventricular twist mechanics in patients with apical hypertrophic cardiomyopathy: assessment with 2D speckle tracking echocardiography.

OBJECTIVE: Left ventricular (LV) apical rotation significantly contributes to LV twist, which has been reported to have a vital role in maintaining LV systolic and diastolic function. Apical hypertrophic cardiomyopathy (ApHCM) is a unique disease with pathological LV hypertrophy at the apex. We aimed (1) to evaluate LV twist mechanics in ApHCM and (2) to demonstrate the influence of predominantly local, pathological involvement of the apical myocardium on LV twist mechanics. METHODS: 21 patients diagnosed with ApHCM were consecutively enrolled and compared with normal controls. After a standard echocardiographic examination, we scanned parasternal basal and apical short-axis planes to quantify LV rotations and LV twist using the speckle tracking technique. For better understanding of LV twist mechanics in ApHCM, LV radial and biplanar strains and LV twist-volume curve were also evaluated. RESULTS: Compared with the normal controls, apical rotation was markedly decreased in ApHCM patients (p<0.001), but the decreases in basal rotation were not significant. As a consequence, LV twist was significantly lower in ApHCM patients (p = 0.007). Apical radial (p = 0.01) and biplanar (p<0.001) strains in ApHCM were also significantly decreased. Compared to normal controls, LV twist-volume and twist-radial displacement curves clearly showed a decrement in the slope of the linear systolic phase and a loss of an inflection point separating the early from late untwisting phase in ApHCM patients. CONCLUSION: LV twist in ApHCM was significantly decreased due to a reduction in apical rotation, suggesting that regional myocardial changes in ApHCM can modify the global LV twist mechanics. Given the close interconnection between LV systolic and diastolic function, impairment of LV twist may lead to the loss of early diastolic suction and finally generate diastolic dysfunction in ApHCM.

The effect of granulocyte-colony stimulating factor on endothelial function in patients with myocardial infarction.

OBJECTIVE: The effects of granulocyte-colony stimulating factor (G-CSF) on endothelial function are unknown. Therefore, we investigated the effects of G-CSF on endothelial function. METHODS: 76 patients participating in the MAGIC-Cell-3-DES trial were enrolled. These were patients with acute myocardial infarction (AMI) or old MI (OMI) who underwent percutaneous coronary intervention (PCI), and were prospectively randomised into a G-CSF group (G-CSF (10 microg/kg/day) injection for 3 days after PCI) or a control group. Additionally, 20 healthy volunteers were also enrolled. These subjects were categorised into five groups: AMI-control (n = 18), AMI-G-CSF (18), OMI-control (20), OMI-G-CSF (20) and healthy-G-CSF (20). Baseline flow-mediated dilation (FMD) of the brachial artery and serum inflammatory biomarkers were performed on day 1, and repeated on day 4 in all groups. G-CSF was injected for 3 days between days 1 and 4 in the AMI-G-CSF, OMI-G-CSF and healthy-G-CSF groups. RESULTS: In both the healthy-G-CSF and OMI-G-CSF groups, G-CSF increased serum high sensitivity C-reactive protein (hsCRP) (0.3 (0.5) mg/l vs 6.1 (3.5) mg/l and 5.6 (3.8) mg/l vs 13.0 (7.7) mg/l, baseline vs post-G-CSF in the healthy and OMI-G-CSF groups, respectively, p<0.001). In the AMI-G-CSF group, G-CSF hindered the decline of hsCRP during the recovery phase, resulting in a relative increase in hsCRP. However, in all three groups, G-CSF did not significantly alter FMD. CONCLUSION: Despite an associated increase in systemic inflammation, G-CSF treatment does not lead to acute impairment of brachial artery endothelial function in either healthy subjects or patients with MI.

Interactive effect of central obesity and hypertension on cognitive function in older out-patients with Type 2 diabetes.

AIM: Central obesity, hypertension and diabetes mellitus have been related individually to cognitive dysfunction. We aimed to study the interactive effects of these co-occurring risk factors on cognitive decline, which remain unclear in older patients with diabetes. METHODS: We assessed metabolic profiles and neuropsychological functions in 60 older out-patients with Type 2 diabetes to examine the associations of central obesity with cognitive functions, while controlling for other confounding factors in these subjects. RESULTS: Waist circumference was associated with poor performance in digits forward (r2 = 0.11, P = 0.02), choice reaction time (r2 = 0.08, P = 0.04) and cognitive reaction time (r2 = 0.07, P < 0.05) even after adjustment for potential confounders including age, gender, education and HbA1c. There were also significant interactions between central obesity and hypertension with respect to performance of digits forward (P = 0.04) and delayed verbal cued recall (P = 0.03). CONCLUSION: Our findings suggest that, in addition to glycaemic control, central obesity and hypertension influence cognitive functions, such as attention and psychomotor speed in older patients with Type 2 diabetes.

Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling.

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis in tumor cells and holds a promise as a therapeutic agent against cancer. To elucidate the death signaling evoked by TRAIL, we performed a functional genetic screening and rescued TRAIL-resistant Jurkat clones harboring ribosomal protein S6 (rpS6) cDNA in anti-sense frame. Reduction of rpS6 expression in Jurkat and HeLa cells attenuated apoptosis induced by TRAIL, but not those by other cell death signals, including tumor necrosis factor-alpha and cycloheximide, etoposide, doxorubicin, tunicamycin and staurosporine. Death receptor (DR) 4, but not DR5, was downregulated in rpS6 knockdown cells. Conversely, the sensitivity to TRAIL was increased by the ectopic expression of wild-type rpS6 and further by phospho-defective rpS6 mutant (S6-SS235,6AA), but not by phospho-mimic rpS6 mutant (S6-SS235,6DD). Also, unphosphorylatable rpS6 knock-in mouse embryo fibroblasts (rpS6(P-/-) MEFs) were more sensitive to TRAIL than control MEFs. In addition, SKHep-1 tumor cells, which express less phospho-rpS6 and are more sensitive to TRAIL than other tumor cells, became effectively desensitized to TRAIL after rpS6 knockdown. These results suggest that rpS6, especially in its unphosphorylated form, is a selective mediator of TRAIL-induced apoptosis.

An ion optics study for KSTAR neutral beam injector development.

Ion optics of three accelerator geometries was studied in terms of an analytic linear optics analysis, a numerical simulation using the IGUN program, an optical multichannel measurement of Doppler-shifted H(alpha) lines, and a water-flow calorimetry on the beam absorbing target. In general, there was a reasonable agreement observed between the four analysis methods and thus the theoretical analyses can be utilized with confidence for design iteration.

Effects of stem cell therapy with G-CSF on coronary artery after drug-eluting stent implantation in patients with acute myocardial infarction.

OBJECTIVE: The effects of stem cell therapy on the coronary vasculature were investigated in patients with acute myocardial infarction who underwent peripheral blood stem cell (PBSC) therapy in the MAGIC Cell-3-DES study. METHODS: Among 50 patients with acute myocardial infarction who underwent either sirolimus-eluting stent or paclitaxel-eluting stent implantation for the culprit lesion, intravascular ultrasound was analysed in 36 patients (cell infusion: n = 19 and control: n = 17). In the cell infusion group, PBSCs mobilised by granulocyte-colony stimulating factor were delivered via intracoronary infusion into infarcted myocardium. Proximal and distal reference segments, and stented segments, were evaluated with intravascular ultrasound at immediate post-intervention and 6-month follow-up, respectively. RESULTS: In the proximal and distal reference segments, the serial changes of lumen area, vessel area, and plaque plus media area were not significantly different between the cell infusion and the control groups. Within stented segments, mean neointimal area was similar in the two groups (cell infusion: 0.2 (SD 0.5) mm(2) vs control: 0.3 (SD 0.4) mm(2), p>0.05). However, there was a significant increase in mean peri-stent area of stented segment in the cell infusion group compared with the control group (0.7 (SD 1.4) mm(2) vs -0.1 (SD 1.2) mm(2), p<0.05). This difference mainly came from paclitaxel-eluting stent-implanted patients. CONCLUSION: Intracoronary infusion of PBSCs mobilised with G-CSF does not aggravate de novo atherosclerotic lesion and neointimal hyperplasia with DES implantation. However, it may induce peri-stent tissue growth at the stented segment, especially in patients receiving PES. Its clinical significance needs to be evaluated with long-term follow-up.

Restoration of left ventricular synchronous contraction after acute myocardial infarction by stem cell therapy: new insights into the therapeutic implication of stem cell therapy for acute myocardial infarction.

OBJECTIVE: To evaluate the effects of stem cell therapy on restoration of the left ventricular (LV) synchronous contraction in patients with acute myocardial infarction (AMI). METHODS: 40 patients with AMI who underwent successful coronary revascularisation were randomly allocated to the cell infusion or the control group. Evaluations were performed with echocardiographic tissue synchronisation imaging to determine LV dyssynchrony and with cardiac magnetic resonance imaging to estimate LV ejection fraction (LVEF) at baseline and at 6 months. To quantify the severity of systolic LV dyssynchrony, the standard deviations of time to peak systolic velocity of the 12 LV segments (Ts-SD) were calculated. RESULTS: At 6 months, greater improvements of Ts-SD (DeltaTs-SD: -45.0 (40.2) vs 5.0 (39.9) ms, p<0.001) and LVEF (DeltaLVEF: 6.8% (9.1%) vs -0.2% (6.9%), p = 0.015) relative to the corresponding baseline values were observed in the cell infusion group than in the control group. By multivariate analysis, DeltaTs-SD and baseline LVEF emerged as the independent determinants of LVEF improvement and cell infusion, and baseline Ts-SD as the determinant of DeltaTs-SD improvement. Maximal exercise capacity measured by symptom-limited treadmill testing correlated well with Ts-SD but not with LVEF at 6 months of follow-up. CONCLUSION: Stem cell therapy had a favourable effect on the restoration of LV synchronous contraction in patients with AMI.

Prognostic significance of asymptomatic coronary artery disease in patients with diabetes and need for early revascularization therapy.

AIMS: Information on the clinical outcome of patients with diabetes with silent myocardial ischaemia is limited. We compared the clinical and angiographic characteristics, and the clinical outcomes of diabetic patients with asymptomatic or symptomatic coronary artery disease (CAD). METHODS: Three hundred and ten consecutive diabetic patients with CAD were divided into two groups according to the presence of angina and followed for a mean of 5 years. Fifty-six asymptomatic patients with a positive stress test and CAD on coronary angiography were compared with 254 symptomatic patients, 167 with unstable angina and 87 with chronic stable angina. RESULTS: Although the severity of coronary atherosclerosis was similar in asymptomatic and symptomatic patients, revascularization therapy was performed less frequently in the asymptomatic than the symptomatic patients (26.8 vs. 62.0%; P < 0.001). Asymptomatic patients experienced a similar number of major adverse cardiac events (MACEs; death, non-fatal myocardial infarction, and revascularization; 32 vs. 28%; P = 0.57), but had higher cardiac mortality than symptomatic patients (26 vs. 9%; P < 0.001). However, patients who underwent revascularization therapy at the time of CAD diagnosis in these two groups showed similar MACE and cardiac mortality (20.0 vs. 22.5%, 6.7 vs. 5.3%, respectively; all P > 0.05). CONCLUSIONS: This study suggests that diabetic patients with asymptomatic CAD have a higher cardiac mortality risk than those with symptomatic CAD, and that lack of revascularization therapy may be responsible for the poorer survival.