High-target Group Research Articles

The effect of oxygen saturation targeting on retinal blood vessel growth using retinal image data from the BOOST-II UK Trial.

PurposeRetinopathy of prematurity (ROP) is a disorder of developing retinal blood vessels in preterm infants. The purpose of this nested study was to investigate the effects of higher (91–95%) and lower (85–89%) oxygen saturation (SpO2) targeting on retinal blood vessel growth in preterm infants.MethodsRetinal blood vessel growth in the higher (91–95%) and lower (85–89%) oxygen saturation (SpO2) targeting groups was compared. Suitable RetCam (Clarity, Pleasanton, CA, USA) images collected in the BOOST-II UK trial were used. The distances between the centre of the optic disc and the ROP ridge in the temporal and nasal retina were measured in pixel units.ResultsImages from 38 infants were studied, 20 from the higher SpO2 target group and 18 from the lower SpO2 target group. On average, temporal blood vessels extended further from the optic disc than nasal blood vessels, mean (standard deviation (SD)) 463.39 (55.05) pixels compared with 360.13 (44.47) pixels, respectively, P<0.0001. Temporal blood vessels extended less far from the optic disc in the higher SpO2 target group than in the lower SpO2 target group: mean (SD) 449.83 (56.16) pixels compared with 480.02 (49.94), respectively, P=0.055. Nasal retinal blood vessel measurements were broadly similar in the higher and lower SpO2 target groups; mean (SD) 353.96 (41.95) compared with 370.00 (48.82) pixels, respectively, P=0.38.ConclusionsRelatively high oxygen saturation targeting (91–95%) was associated with a trend (P=0.055) towards reduced retinal blood vessel growth in this study of preterm infants.

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial

Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. Deutsche Forschungsgemeinschaft.

Impact of Study Oximeter Masking Algorithm on Titration of Oxygen Therapy in the Canadian Oxygen Trial

To compare oxygen saturations as displayed to caregivers on offset pulse oximeters in the 2 groups of the Canadian Oxygen Trial. In 5 double-blind randomized trials of oxygen saturation targeting, displayed saturations between 88% and 92% were offset by 3% above or below the true values but returned to true values below 84% and above 96%. During the transition, displayed values remained static at 96% in the lower and at 84% in the higher target group during a 3% change in true saturations. In contrast, displayed values changed rapidly from 88% to 84% in the lower and from 92% to 96% in the higher target group during a 1% change in true saturations. We plotted the distributions of median displayed saturations on days with >12hours of supplemental oxygen in 1075 Canadian Oxygen Trial participants to reconstruct what caregivers observed at the bedside. The oximeter masking algorithm was associated with an increase in both stability and instability of displayed saturations that occurred during the transition between offset and true displayed values at opposite ends of the 2 target ranges. Caregivers maintained saturations at lower displayed values in the higher than in the lower target group. This differential management reduced the separation between the median true saturations in the 2groups by approximately 3.5%. The design of the oximeter masking algorithm may have contributed to the smaller-than-expected separation between true saturations in the 2 study groups of recent saturation targeting trials in extremely preterm infants.

Optimum Blood Pressure Target After Lacunar Stroke

The recent report of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a randomized controlled clinical trial of secondary prevention of stroke targeting systolic blood pressures (BPs) <130 versus 130 to 149 mm Hg in patients with recent but not acute subcortical lacunar stroke,1 and the associated Comment2 conclude that “Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial.”1 Indeed, the Comment underlined that “the SPS3 trial was underpowered to identify or exclude confidently a slight, but nevertheless clinically important, increase in serious complications of hypotension with systolic blood pressure lower than 130 mm Hg.”2 However, the cover of August 10 to 16, 2013 issue of The Lancet that carries the article on SPS3 and the associated Comment reads “The implications of SPS3 are that clinicians should endeavour to achieve and maintain systolic blood pressures lower than 130 mm Hg in patients who have survived 2 weeks or more after subcortical lacunar ischemic stroke.” This assertion is essentially based on the consistency of results across subgroups, the consistency of results (19% reduction in events) with other studies of primary or secondary prevention of different types of stroke, at similar differences of systolic BP between groups, in this particular trial 11 mm Hg between the achieved BP of the high-target group (138 mm Hg) and the low-target group (127 …

High versus Low Blood-Pressure Target in Patients with Septic Shock

BackgroundThe Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.MethodsIn a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28.ResultsAt 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality.ConclusionsTargeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.)

G125(P) Oxygen saturation target monitoring in preterm babies: A survey of level 3 units in United Kingdom

BackgroundPulse oximetry is widely used for monitoring oxygen saturation, but uncertainty remains as to most appropriate target range in preterm babies. Studies have been conducted and various target limits have...

작업관련성 손상·질병 발생과 손실비용에 따른 예방정책 우선순위 연구

As workplace incidents has been being declining in Korea, there is criticism of the effectiveness of occupational safety policy implementation. It is unknown that which policy target group needs to be targeted to yield effective injuries prevention. The purpose of this paper is to analyze and reveal the policy intervention group with a high priority in terms of industrial incident prevention and the related investment cost. A Policy Priority Model(PPM) is composed of 6 indicators regarding influences of both the incident reduction and the cost reduction. Z-score analyses are used to confirm the high policy priority area or policy target group. Overall, workplace with worker below 50 persons, construction site with the sales of more than a hundred million won, workplace with relatively small percentage of female employees and relatively higher percentage of older worker should be prioritized to reduce workplace injuries. This paper provides an analytic way that can be used to decide the policy priority workplace in order not only to reduce work-related injuries&illnesses and the related investment cost but to further lessen the related societal costs.

Oxygen Saturation and Outcomes in Preterm Infants

BackgroundThe clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used.MethodsIn three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes.ResultsA total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events.ConclusionsTargeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.)

ESAs in Transplant Anemia

ESAs in Transplant Anemia

Effect of Presentation of Target on the Physical Performance in Healthy Subjects: A Preliminary Study

Purpose: This study investigates the effect of presenting the target as an intrinsic reward on the physical performance of healthy subjects. Methods: Fifteen healthy people (62.9 ± 11.6 years old, mean ± standard deviation; 6 females and 9 males) were enrolled in this study. The task for physical performance was the Functional Reach Test, and participants performed the pre- and post-test. Participants were assigned randomly to a Control group, a High Target group (HT group) or Low Target group (LT group). In the control group, participants received feedback about each result and encouragement. In the HT group, participants received feedback about each result and were presented a target score that increased the result by 20%. In the LT group, participants received feedback about each result and were presented the target score that decreased the result by 20%. Results: The main effect of group was no significance (p=0.88). The main effect of time was significant (p=0.011). The group × time interaction was no significance (p=0.13). The post hoc test that compared the pre-test and post-test within each group was significant only in the HT group (p<0.05). Conclusion: The results of this preliminary study indicate that physical performance in healthy people improved by presenting a set target, as well as feedback of the result. In particular, the results showed that a high target slightly beyond each result was more desirable than a low target. Together, our results suggest that the presentation of a set target as an intrinsic reward may improve physical performance and motivation.

Effects of Methylene Blue and Volatile Anesthetics on Survival in a Murine Hemorrhage Resuscitation Model

Hemorrhage is a frequent cause of morbidity and mortality, possibly complicated by volatile anesthetics administered during surgical emergencies. Because methylene blue (MB) was suggested to reduce bleeding, we reasoned that it may improve resuscitation. We used a rat model of controlled and uncontrolled hemorrhage with fluid resuscitation, aiming at high versus low mean arterial pressure (MAP) to assess the role of early MB injection on survival and the effects of different anesthetics on outcome. Wistar male rats (n = 160) were subjected to 15-minute controlled and 60-minute uncontrolled hemorrhage and received lactated Ringer's solution replacement. Four sets (four groups per set, N = 10 per group) were anesthetized with halothane, isoflurane, sevoflurane, or ketamine (KET; control). Resuscitation-targeted MAP was 80 mm Hg in two groups per set and 40 mm Hg in two groups per set: one group received MB 25 mg/kg intravenously and the other one did not receive. All parameters were worse in the higher target groups compared with the lower MAP target groups. MB improved variable outcomes in the treated compared with the nontreated groups, independent of the MAP or anesthesia agent: the amount of replacement volume, lung tissue xanthine oxidase activity, and rats' survival rates. Outcomes with and without MB were worse in the halothane set, followed, in ascending order, by sevoflurane, isoflurane, and KET. MB improved parameters and survival rates after controlled and uncontrolled hemorrhage and fluid resuscitation, even in high MAP-resuscitated rats. KET seemed to be the best anesthetic choice among the four classic agents tested. The effects of balanced anesthesia and total intravenous anesthesia in similar conditions require additional studies.

Erythropoietin Therapy, Hemoglobin Targets, and Quality of Life in Healthy Hemodialysis Patients

The effects of different hemoglobin targets when using erythropoiesis-stimulating agents on quality of life are somewhat controversial, and predictors of change in quality of life in endstage renal disease have not been well characterized. Five hundred ninety-six incident hemodialysis patients without symptomatic cardiac disease were randomly assigned to hemoglobin targets of 9.5 to 11.5 g/dl or 13.5 to 14.5 g/dl for 96 weeks, using epoetin_alfa as primary therapy. Patients and attending physicians were masked to treatment assignment. Quality of life, a secondary outcome, was prospectively recorded using the Kidney Disease Quality of Life (KDQoL) questionnaire at weeks 0, 24, 36, 48, 60, 72, 84, and 96, with prespecified outcomes being fatigue and quality of social interaction. The mean age and prior duration of dialysis therapy of the study population were 50.8 and 0.8 yr. Mortality was low, reflecting the relatively healthy group enrolled. Of 20 domains within the KDQoL only the prespecified domain of fatigue showed significant change over time between the two groups. Improvement in fatigue scores in the high-target group ranged from 3.2 to 7.9 over time (P = 0.007) compared with change in the low-target group. Higher body mass index and lower erythropoietin dose at baseline were independent predictors of improvement in multiple KDQoL domains. In relatively healthy hemodialysis patients, normal hemoglobin targets may have beneficial effects on fatigue. Improvement in multiple domains of quality of life is associated with higher body mass index and lower erythropoietin requirements.

Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis

Recombinant human erythropoietin is commonly used for treatment of anaemia. Our aim was to determine whether targeting different haemoglobin concentrations with such treatment is associated with altered all-cause mortality and cardiovascular events in patients with anaemia caused by chronic kidney disease. We did a meta-analysis of randomised controlled clinical trials that were identified in medical databases and trial registration websites. Trials were eligible for inclusion if they assessed the effects of targeting different haemoglobin concentrations in patients with anaemia caused by chronic disease who were randomly assigned to treatment with recombinant human erythropoietin, recruited at least 100 patients, and had a minimum follow-up of 12 weeks. We analysed nine randomised controlled trials that enrolled 5143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1.17, 95% CI 1.01-1.35; p=0.031) and arteriovenous access thrombosis (1.34, 1.16-1.54; p=0.0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1.27, 1.08-1.50; p=0.004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, this was not significant in the random effects model (1.31, 0.97-1.78; p=0.075). The incidence of myocardial infarction was much the same in the two groups. To target higher haemoglobin concentrations when treating patients with anaemia caused by chronic kidney disease with recombinant human erythropoietin puts such patients at increased risk of death. Current guidelines do not include an upper limit for the target haemoglobin concentration; such an upper limit should be considered in future recommendations.

Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients

The required erythropoiesis-stimulating agent (ESA) dose varies when correcting anaemia in chronic kidney disease (CKD) patients. This analysis was performed to identify the prevalence of and factors associated with ESA hyporesponsiveness. This analysis was a post hoc evaluation of epoetin alfa dosage requirements in a subgroup of patients from the Effect of early Correction of Anemia on the Progression of CKD study. The patients in this subgroup were randomly assigned to the high haemoglobin target group (14-15 g/dl for men and 13-14 g/dl for women) and completed a 4-month haemoglobin stabilization phase with complete epoetin dosage data. The relationship of demographics, disease characteristics and laboratory measures with epoetin dosage were evaluated using Pearson's correlation, association measures and analysis of covariance (ANCOVA) models. Of the 93 patients evaluated in this subgroup analysis, 14 (15%) were hyporesponsive to epoetin (maximum dosage >100 IU/kg/week during stabilization). An ANCOVA analysis showed that 52% of the observed variability in epoetin dosage at completion of the stabilization phase could be accounted for by diabetes as the primary cause of kidney disease, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) use, proteinuria, transferrin saturation, age, pre-treatment haemoglobin, geographical region, serum iron and body mass index (BMI). Unidentified patient characteristics accounted for an additional 16% of the dosage variance. Older age, higher BMI, anaemia, ACE inhibitor/ARB use and diabetes as the primary cause of kidney disease are associated with increased epoetin requirements when normalizing haemoglobin in anaemic CKD patients.

Using Contingent Valuation in Hypothetical Settings: Estimating the WTP for an HIV/AIDS Vaccine

A contingent valuation survey was carried out to assess willingness to pay (WTP) for an HIV/AIDS vaccine. The survey was conducted among students at the University of KwaZulu-Natal (UKZN), Durban. The payment card method was used to elicit willingness to pay estimates. Questions on demographics, socio-economic status, sexual behaviour, HIV risk and HIV testing were also collected and analysed in an ANOVA regression model to determine their effect on the WTP variable. Among the respondents, 71.5% would want to be vaccinated at a mean WTP of $108 (R648) and median of $33.4 (R200). The most common reasons for not wanting to be vaccinated were concerns about the safety of the vaccine and a low perceived risk of contracting HIV. Higher ability to pay (higher monthly income) was positively associated with WTP. Having been tested for HIV before and being female were both found to decrease WTP. While the limits of the willingness to pay method were acknowledged, the results have important implications regarding investment decisions into vaccine research and development as well as the design of marketing campaigns for a future AIDS vaccine. Indeed this is the first study asking such questions for a potential high risk specific target group of 16–24 year old adults.

Using Healthcare Administrative Data to Identify High Priority Target Groups for Influenza Vaccination

Using Healthcare Administrative Data to Identify High Priority Target Groups for Influenza Vaccination

Double-Blind Comparison of Full and Partial Anemia Correction in Incident Hemodialysis Patients without Symptomatic Heart Disease

It is unclear whether physiologic hemoglobin targets lead to cardiac benefit in incident hemodialysis patients without symptomatic heart disease and left ventricular dilation. In this randomized, double-blind study, lower (9.5 to 11.5 g/dl) and higher (13.5 to 14.5 g/dl) hemoglobin targets were generated with epoetin alpha over 24 wk and maintained for an additional 72 wk. Major eligibility criteria included recent hemodialysis initiation and absence of symptomatic cardiac disease and left ventricular dilation. The primary outcome measure was left ventricular volume index (LVVI). The study enrolled 596 patients. Mean age, duration of dialysis therapy, baseline predialysis hemoglobin, and LVVI were 50.8 yr, 0.8 yr, 11.0 g/dl, and 69 ml/m2, respectively; 18% had diabetic nephropathy. Mean hemoglobin levels in the higher and lower target groups were 13.3 and 10.9 g/dl, respectively, at 24 wk. Percentage changes in LVVI between baseline and last value were similar (7.6% in the higher and 8.3% in the lower target group) as were the changes in left ventricular mass index (16.8 versus 14.2%). For the secondary outcomes, the only between-group difference was an improved SF-36 Vitality score in the higher versus the lower target group (1.21 versus -2.31; P = 0.036). Overall adverse event rates were similar in both target groups; higher (P < 0.05) rates of skeletal pain, surgery, and dizziness were seen in the lower target group, and headache and cerebrovascular events were seen in the higher target group. Normalization of hemoglobin in incident hemodialysis patients does not have a beneficial effect on cardiac structure, compared with partial correction.

Applied Behavior Change: A framework for behavior change interventions and research

Drug abuse is a worldwide problem, affecting lesser developed as well as developed countries. Demand in some developing countries, particularly those engaged in narcotics production and trafficking, is growing much more rapidly than in developed countries. For example, Colombia estimates that it has over 600,000 cocaine and/or coca paste abusers, while Peru claims about 138,000. In Bolivia, as many as 11% of youth, ages 12-15, may be habitual consumers of illicit drugs. In Pakistan, the estimated number of heroin addicts was 5000 in 1980; by 1986, it was 600,000, and numbers may now exceed a million. Thailand estimates 300-500,000 heroin addicts, nearly as many as the US (Drug Data). Specific problem drugs and abuse behaviors vary across countries and cultures, as do the responses of policymakers, health educators, and concerned communities. But the demand for prevention as well as control programs is increasing. As a result, the US Agency for International Development (USAID) is becoming more involved in drug awareness and education programs as an element of its overall anti-narcotics program. In the Latin America and Caribbean region, 12 USAID Missions support drug awareness and education programs. In the Asia and Near East region, USAID has supported one regional and several bilateral programs. USAIDs prevention program encompasses objectives at three levels. First, awareness by developing country policymakers of the drug threat at home serves as a powerful motivator for policy actions essential to stemming drug production, processing, and trafficking; a major US policy objective. Secondly, well-designed programs of public education build grassroots support within developing countries for domestic drug control and prevention efforts. Thirdly, carefully targeted behavior change interventions prevent, delay, or reduce the substance abuse behaviors of high risk target groups in the participating developing countries, and therefore foster a partnership between US and developing country policymakers in the global struggle against drug abuse at all levels. This review will focus principally on the third objective, targeted behavior change interventions. The three levels of prevention represent three different behavioral challenges. Primary prevention focuses on at-risk populations prior to first trial of drugs.

Improvement in infant and perinatal mortality in the United States, 1965--1973: I. Priorities for intervention.

Changes in United States infant and perinatal mortality in the period 1965--1973 were examined by race, age at death or length of gestation, and degree of urbanization. The decline of postneonatal mortality rates was greater than the declines of fetal and neonatal mortality rates. Other-than white infant and fetal mortality rates improved more than the white rates, except in the first day of life. Postneonatal mortality rates improved more in rural than in urban areas, while neonatal and perinatal mortality rates improved more in urban areas than in rural. These improvements in mortality rates have occurred at the same time as changes in medical techniques and the organization and availability of health services, improvements in economic conditions and standards of living, and changes in the demographic characteristics of the child-bearing population of the United States. Each of these changes was in a direction expected to have a favorable effect on infant and perinatal mortality. Nevertheless, the improvement of infant mortality rates has not changed the relative position of the United States in comparison with other countries. Programs to improve infant and perinatal mortality can use the data in this study to define high priority target groups using a method based on the size of the problem in the target group, the severity of the problem, and the amount and direction of change.