Relationship of nocturnal hypoglycemia to daytime glycemia in IDDM.

In view of the continuing debate about the clinical relevance of nocturnal hypoglycemia as an explanation for high blood glucose (BG) levels before breakfast, we prospectively analyzed 281 overnight BG profiles (blood samples obtained at 2100, 0200-0300, and 0700) in 66 consecutive patients with insulin-dependent diabetes mellitus. Nocturnal hypoglycemia (0200-0300 BG concentration less than or equal to 50 mg/dl) occurred in 27 patients (41%) and in 36 profiles (13%). All the patients with nocturnal hypoglycemia received two or more injections of insulin each day. When hypoglycemia occurred at 0200-0300, the preceding BG concentration at 2100 was significantly lower than when nocturnal BG was greater than 100 mg/dl (108 +/- 11 vs. 145 +/- 12 mg/dl; P less than .05; mean +/- SE). A BG less than or equal to 120 mg/dl at 2100 preceded nocturnal hypoglycemia in 24 (67%) of 36 profiles. The mean BG at 0700 was significantly lower in the profiles associated with nocturnal hypoglycemia than in those with nocturnal BG levels greater than 150 mg/dl (156 +/- 10 vs. 201 +/- 11 mg/dl; P less than .05). BG values greater than 180 mg/dl at 0700 were infrequently (11 of 143 or 8% of profiles) preceded by nocturnal hypoglycemia, and no instances of major hyperglycemia (BG greater than 300 mg/dl) at 0700 were preceded by nocturnal hypoglycemia. Furthermore, BG at 0700, 1100, and 1500 on the day before the occurrence of nocturnal hypoglycemia were similar to those on the day after.(ABSTRACT TRUNCATED AT 250 WORDS)

Screening for thyroid disease in children with IDDM.

The aim of this study was to evaluate the usefulness of screening for thyroid disease by performing thyroid function tests and measuring thyroid autoantibodies in 371 children and adolescents with insulin-dependent diabetes mellitus (IDDM). We analyzed clinical data and results of serum thyroxine, triiodothyronine uptake, thyroid-stimulating hormone, and antibodies to thyroid microsomal antigen and thyroglobulin. Goiter was noted in 20% of subjects. Thyroid-specific autoantibody was positive in 19% of subjects. Twenty-seven subjects (7%) had thyroid dysfunction. Autoantibody testing identified subjects with thyroid dysfunction with a sensitivity of 50%, a specificity of 84%, a degree of misclassification of 17%, a positive predictive value of 13%, and a negative predictive value of 97%. We recommend that all children and adolescents be screened shortly after diagnosis of IDDM by determination of thyroid-stimulating hormone (measured by high-sensitivity assay) to identify thyroid dysfunction and by testing for antibody to thyroid microsomal antigen to characterize both risk of future thyroid dysfunction and the need for future testing.

Split-mixed insulin regimen with human ultralente before supper and NPH (isophane) before breakfast in children and adolescents with IDDM.

OBJECTIVE: Fasting hyperglycemia is common in patients with insulin-dependent diabetes mellitus (IDDM) treated with twice-daily subcutaneous insulin regimens. We postulated that substituting human ultralente insulin for the presupper dose of intermediate-acting insulin would improve overnight glycemic control in children and adolescents with IDDM. RESEARCH DESIGN AND METHODS: This 6-mo double-blind crossover study compared a conventional insulin regimen, a mixture of human NPH and regular given before both breakfast and supper (NPH), with a novel twice-daily regimen in which human ultralente replaced NPH before the evening meal (ultralente). This study was comprised of 20 children and adolescents (mean age and duration of IDDM 11.3 +/- 2.9 and 2.4 +/- 1.3 yr, respectively) from the Youth Clinic of the Joslin Diabetes Center, all of whom regularly performed self-monitoring of blood glucose (SMBG) and had been treated exclusively with human insulin (mean daily dose 0.75 +/- 0.22 U/kg). Subjects performed SMBG on a prescribed schedule with a glucose meter with an electronic memory, and recorded results of blood glucose measurements, insulin dosages, and episodes of hypoglycemia. Monthly measurements were obtained for height, weight, and HbA1, and mean daily insulin dosages and average blood glucose level before breakfast, lunch, supper, bedtime snack, and between 0200 and 0300 were calculated. Nonfasting serum lipids were measured at entry, crossover, and the end of the study. RESULTS: After 3 mo, mean HbA, did not differ significantly (9.1 +/- 1.7 vs. 9.5 +/- 1.4%, NPH and ultralente, respectively). Mean fasting blood glucose was significantly lower on ultralente (9.6 +/- 1.9 vs. 10.3 +/- 2.2 mM, P less than 0.05, and blood glucose showed a similar trend (0.05 less than P less than 0.1) before lunch (8.9 +/- 1.7 vs. 9.8 +/- 2.6 mM. Mean blood glucose before bedtime snack was significantly lower (P less than 0.01) on NPH (8.4 +/- 1.9 vs. 10.0 +/- 2.1 mM) but did not differ significantly before supper or between 0200 and 0300. On the two regimens, growth and serum lipids were normal and similar, and no differences were observed in the incidence or severity of hypoglycemia. CONCLUSIONS: Compared with a mixed dose of regular and NPH, a similar dose of a mixture of regular and human ultralente insulin before supper caused a modest reduction in fasting blood glucose levels but was associated with higher blood glucose levels before the bedtime snack. Overall glycemic control, reflected in HbA1 values, was not significantly improved.

Clinic attendance and glycemic control. Study of contrasting groups of patients with IDDM.

OBJECTIVE: To assess factors associated with attendance at a specialized clinic for diabetes care. RESEARCH DESIGN AND METHODS: Adults with insulin-dependent diabetes mellitus (IDDM) in poor (HbA1 greater than or equal to 12%) versus good (HbA1 less than or equal to 10%) control and with no known complications comprised the study group. RESULTS: Infrequent attenders were in worse glycemic control than regular attenders (chi 2 = 6.60, P less than or equal to 0.01) and held health beliefs that downplayed the importance of getting advice from physicians (P less than or equal to 0.002) or providing opinions to physicians about what might be done to improve their health (P less than or equal to 0.001). CONCLUSIONS: Because infrequent attenders are more likely to be in poor glycemic control and thus at greater risk for diabetic complications, engaging them in regularly supervised treatment has important personal and public health implications. Additional studies are needed to understand why some diabetic patients limit their contact with medical providers and to develop more effective strategies for reversing this process. Initial findings from this study suggest that patient beliefs about the doctor-patient relationship may influence clinic attendance.

Psychological adjustment of children with recently diagnosed diabetes mellitus.

Children with recent onset of insulin-dependent diabetes mellitus (IDDM) were compared with a sample of children with a recent acute medical problem. No differences were found in terms of self-esteem, locus of control, behavioral symptoms, or social functioning. A separate assessment of adjustment to diabetes was strongly correlated with each of these general personality, behavioral symptom, and social functioning measures. Sociodemographic factors such as age, gender, and social class did not predict the level of adjustment to diabetes. This study suggests that onset of diabetes does not necessarily lead to major disruptions of psychological adaptation. It also affirms the view that early adjustment to diabetes is embedded in a context of overall personality development and adaptation.

Psychological characteristics of adults with IDDM. Comparison of patients in poor and good glycemic control.

This study was conducted to evaluate selected psychosocial characteristics of contrasting groups of patients with insulin-dependent diabetes mellitus (IDDM), i.e., patients with persistently poor versus good glycemic control. Patients with chronic poor control reported feeling physically best at higher blood glucose levels than patients with good control. They also reported a higher threshold for physical symptoms caused by hyperglycemia without any difference in threshold for hypoglycemic symptoms. No differences between groups were found in level of diabetes knowledge, self-esteem, or psychiatric symptomatology. This study suggests that poorly controlled adult patients have underlying perceptions of hyperglycemic symptoms and physical well-being that distinguish them from patients with well-controlled diabetes. The design of this study does not allow for determination of the causal direction in this relationship. Although these patient reports about glycemic and physical symptoms may be post hoc justifications or unreliable beliefs, they also may be accurate perceptions of physical symptom experiences and therefore could influence their self-care activities with resulting chronic problems in glycemic control. Further research is needed to assess the validity of these observations and their possible role in long-term regulation of glycemia.

Psychological adjustment to IDDM: 10-year follow-up of an onset cohort of child and adolescent patients.

OBJECTIVE: To evaluate the psychological adjustment of young adults with IDDM in comparison with similarly aged individuals without chronic illness. RESEARCH DESIGN AND METHODS: An onset cohort of young adults (n = 57), ages 19-26 years, who have been followed over a 10-year period since diagnosis, was compared with a similarly aged group of young adults identified at the time of a moderately severe, acute illness (n = 54) and followed over the same 10-year period. The groups were assessed at 10-year follow-up in terms of 1) sociodemographic indices (e.g., schooling, employment, delinquent activities, drug use), 2) psychiatric symptoms, and 3) perceived competence. In addition, IDDM patients were examined for longitudinal change in adjustment to diabetes. RESULTS: The groups differed only minimally in terms of sociodemographic indices, with similar rates of high school graduation, post-high school education, employment, and drug use. The IDDM group reported fewer criminal convictions and fewer non-diabetes-related illness episodes than the comparison group. There were no differences in psychiatric symptoms. However, IDDM patients reported lower perceived competence, with specific differences found on the global self-worth, sociability, physical appearance, being an adequate provider, and humor subscales. The IDDM patients reported improving adjustment to their diabetes over the course of the 10-year follow-up. CONCLUSIONS: Overall, the young adults with IDDM appeared to be as psychologically well adjusted as the young adults without a chronic illness. There were, however, indications of lower self-esteem in the IDDM patients that could either portend or predispose them to risk for future depression or other difficulties in adaptation.

Cornstarch regimens for nocturnal treatment of young adults with type I glycogen storage disease.

The goal of treatment of type I glycogen storage disease (GSD-I) is to prevent hypoglycemia and its biochemical consequences. In seven patients with GSD-I with a mean age of 19.5 y (range: 18.8-21.7 y), we compared the biochemical effects of isoenergetic amounts of uncooked cornstarch (UCS; 1.76 +/- 0.41 g/kg) given in random order on consecutive nights either as a single dose at 2100 (time 0) or as equally divided doses at 2100 and 0200. Over the 10-h period of observation there were significant regimen-by-time interactions for plasma glucose, serum insulin, and blood lactate concentrations. Mean time-averaged plasma glucose (5.8 +/- 0.5 compared with 4.9 +/- 0.9 mmol/L) and serum insulin (244 +/- 93 compared with 151 +/- 57 pmol/L) concentrations from 0 to 360 min were significantly higher after the single dose; blood lactate and serum fatty acid concentrations were not significantly different. At 360 min, mean plasma glucose (4.8 +/- 1.2 compared with 4.7 +/- 1.6 mmol/L) and serum insulin (138 +/- 76 compared with 136 +/- 116 pmol/L) concentrations were virtually identical. After a single dose, plasma glucose concentrations were > or = 3.9 mmol/L for 7 h in five of seven subjects; three subjects were treated for hypoglycemia after 7-9.5 h. With divided doses, plasma glucose concentrations were > or = 3.9 mmol/L for 9 h in six of seven subjects; hypoglycemia occurred at 6 h in one subject. A single dose (1.76 +/- 0.41 g/kg) of UCS at bedtime maintains plasma glucose concentrations > or = 3.9 mmol/L for > or = 7 h in most young adults with GSD-I.

Optimal daytime feeding regimen to prevent postprandial hypoglycemia in type 1 glycogen storage disease.

To determine the optimal daytime dietary regimen for type 1 glycogen storage disease (GSD), we used uncooked cornstarch (UCS) at a basal glucose production rate (GPR) in single and divided doses, with mixed meals at 0700 and 1700 h. This regimen was compared with a 1.5 times larger single dose of UCS at 0700 h, and with dextrose at GPR at 1200 h. Two-hour UCS loads (amount equal to GPR in 2 h) given with a mixed meal at 0700 h and 180 min later maintained mean blood glucose (BG) concentrations at greater than or equal to 4.2 mmol/L for 300 min. BG was significantly greater from 240 to 300 min compared with a single 4-h UCS load, and at 300 min compared with a single 6-h UCS load. Similar effects were noted when the divided UCS regimen was given with a mixed meal at 1700 h, but not when isoenergetic amounts of dextrose were given on the same schedules with a mixed meal at 1200 h. A daytime schedule of six UCS feedings (with the three main meals and 180 min later) at GPR maintains BG at concentrations that should minimize biochemical abnormalities and optimize clinical outcome in patients with GSD.

Physical growth and development of children with type 1 glycogen-storage disease: comparison of the effects of long-term use of dextrose and uncooked cornstarch.

Thirteen patients with type 1 glycogen-storage disease (GSD-1) were studied to compare the effects on biochemical control and growth of 2 y of therapy with intermittent feedings of uncooked cornstarch (UCS) at the fasting glucose production rate and therapy with continuous overnight glucose (COG) and dextrose feedings during the day. Mean biochemical abnormalities for the groups were minimized but not normalized by either COG or UCS. Growth progressed normally when COG was started by 1.2 y of age and normal growth rate was maintained by UCS. Weight increased from 101 +/- 3% ideal body weight at onset of COG to 127 +/- 5% during COG and the first year of UCS therapy but did not increase further in the second year. When growth failure occurred before onset of COG [-3.7 SD score for chronological age (SDSCA)], only partial correction (-1.9 SDSCA) to genetic potential for height occurred. Intermittent feeding of UCS provides an effective alternative to COG for the treatment of GSD-1.

Continuous glucose for treatment of patients with type 1 glycogen-storage disease: comparison of the effects of dextrose and uncooked cornstarch on biochemical variables.

Responses to uncooked cornstarch (UCS), dextrose (Dex), and a 3:1 mixture (UCS:Dex) were determined in seven children with type 1 glycogen-storage disease (GSD-1). UCS maintained blood glucose (BG) and serum insulin concentrations between 3.5 +/- 0.3 and 4.0 +/- 0.4 mmol/L (mean +/- SEM) and 50 +/- 7 and 79 +/- 22 pmol/L, respectively, in six of the seven patients for 4 h. Only four of seven patients completed the 4-h test after UCS:Dex (BG 2.9 +/- 0.3 mmol/L): After Dex, tests had to be stopped in all patients by 150 min after initiation (BG 2.7 +/- 0.4 mmol/L). Two methods of providing dietary glucose overnight, continuous intragastric glucose infusion (COG) and intermittent UCS at 2100 and 0200, were compared by monitoring metabolites and glucoregulatory hormones. The use of UCS in amounts equal to the calculated glucose production rate is an effective method of providing a continuous dietary source of glucose overnight to patients with GSD-1.

Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy.

The glycogen storage diseases are caused by inherited deficiencies of enzymes that regulate the synthesis or degradation of glycogen. In the past decade, considerable progress has been made in identifying the precise genetic abnormalities that cause the specific impairments of enzyme function. Likewise, improved understanding of the pathophysiologic derangements resulting from individual enzyme defects has led to the development of effective nutritional therapies for each of these disorders. Meticulous adherence to dietary therapy prevents hypoglycemia, ameliorates the biochemical abnormalities, decreases the size of the liver, and results in normal or nearly normal physical growth and development. Nevertheless, serious long-term complications, including nephropathy that can cause renal failure and hepatic adenomata that can become malignant, are a major concern in GSD-I. In GSD-III, the risk for hypoglycemia diminishes with age, and the liver decreases in size during puberty. Cirrhosis develops in some adult patients, and progressive myopathy and cardiomyopathy occur in patients with absent GDE activity in muscle. It remains unclear whether these complications of glycogen storage disease can be prevented by dietary therapy. Glycogen storage diseases caused by lack of phosphorylase activity are milder disorders with a good prognosis. The liver decreases in size, and biochemical abnormalities disappear by puberty.

Severe hypoglycemia in youth with insulin-dependent diabetes mellitus: frequency and causative factors.

Hypoglycemia is the most common acute complication of insulin-dependent diabetes mellitus, yet data are sparse concerning its frequency and the factors that predispose children and adolescents to its occurrence. This study was undertaken, during a 2-year period, to determine the frequency of severe hypoglycemia and to identify its causative factors in 196 youth with insulin-dependent diabetes mellitus (mean age and duration of diabetes, 13.5 +/- 4.3 and 4.8 +/- 3.2 years, respectively) treated conventionally. The mean daily insulin dose was 0.85 +/- 0.23 U/kg, and 92% of patients received insulin twice daily. Severe hypoglycemia occurred at least once in 2 years in 29 of 196 (14.8%) patients, of whom 9 (31%) had two or more episodes. The mean level of glycosylated hemoglobin closest to the event was significantly lower than that of patients who did not have severe hypoglycemia, 10.6 +/- 1.8 vs 11.4 +/- 2.0, P less than .02; however, the mean insulin dose, 0.88 +/- 0.19 vs 0.85 +/- 0.23 U/kg every 24 hours, was similar. Severe hypoglycemia occurred with equal frequency during waking and sleeping, and it was not related to the species of insulin used. The use of human insulin, per se, did not increase the risk of severe hypoglycemia. Asymptomatic hypoglycemia was reported significantly more often in those who experienced severe hypoglycemia, 24% vs 8%, P = .01. Severe hypoglycemia was common (12.2 episodes per 100 patient-years), and symptomatic hypoglycemia universal in youth with insulin-dependent diabetes mellitus treated with conventional insulin therapy. Approximately two thirds of episodes were attributable to lapses in the application of basic principles of diabetes self-care.

The diagnosis of insulinoma in a child in the absence of fasting hyperinsulinemia.

This report concerns an 8-year-old girl with fasting hypoglycemia caused by a functional islet cell adenoma. During two separate fasting studies the blood glucose concentrations decreased to abnormally low levels yet the serum concentrations of insulin were consistently within the accepted range of normal. This report illustrates the diagnostic value of three simple functional tests--the inhibitory effect of insulin on ketogenesis and on glycogenolysis and the stimulatory effect of leucine on insulin secretion.

Transcutaneous determination of arterial oxygen tension.

Arterial oxygen tension measurements were performed simultaneously using two different techniques: (1) the conventional method of analyzing a blood sample obtained from the radial artery by means of a Clark electrode and (2) a new method of transcutaneous oxygen tension recording using a newly developed surface electrode containing a built-in heating device to ensure optimal cutaneous perfusion at the site of measurement. Two groups of newborn infants were used as subjects: (1) 70 clinically healthy babies who were tested during normoxia and hyperoxia (breathing 80% to 100% oxygen) and (2) 20 sick preterm and term infants receiving inspired oxygen concentrations of between 21% and 100% during the measurement. Our results indicate a satisfactory accuracy for the transcutaneous oxygen tension measurements in normoxia and hyperoxia (percentage coefficient of variation, 15.9% and 24.1%, respectively). In hypoxia agreement between the two methods varies depending on the degree of circulatory derangement. Overall correlation coefficients were greater than 0.85 in each group.

Pulmonary and extrapulmonary effects of increased colloid osmotic pressure during endotoxemia in rats.

OBJECTIVES: We tested the hypothesis that an increase in the blood colloid osmotic pressure (COP) that is maintained during early-stage endotoxemia may decrease fluid flux across capillaries and may reduce pulmonary and multiple-organ edema. DESIGN: Prospective study. SETTINGS: Research laboratory in a hospital. SUBJECTS: Male albino Sprague-Dawley rats. INTERVENTIONS: Rats were anesthetized with pentobarbital, underwent tracheotomies, were cannulated in the femoral vein and artery, and were randomly assigned to the following four groups comprising 11 rats each: group I, controls (saline solution treatment); group II, albumin treatment (three doses of 1 g/kg 25% human albumin every 2 h); group III, endotoxin treatment with a single IV dose of 4 mg/kg endotoxin; and group IV, endotoxin and albumin-treatment (4 mg/kg endotoxin plus albumin treatment). Experiments lasted for 6 h while fluid intake was equally maintained in all groups. MEASUREMENTS AND RESULTS: COP and other variables were measured every 2 h. To determine the water content of an organ, after the rat was killed, the lung, heart, kidney, intestine, and liver were removed. Albumin treatment alone (group II) generated significant increases in COP (maximum, 58% from the baseline measurement) but did not change the water content of the organ, compared with saline solution-treated controls. Endotoxin-treated rats (group III) developed significant reductions in COP, with significant increases in pulmonary, renal, and heart water content compared with controls. Albumin treatment in endotoxemic rats (group IV) significantly increased the COP without improving the endotoxemia-induced organ edema. Pulmonary edema, however, was increased further, compared with endotoxemia alone. CONCLUSIONS: COP elevation by albumin administration during the early stage of endotoxemia does not ameliorate pulmonary or multiple-organ edema and may aggravate pulmonary edema.

Effect of hypothermia on ventilation in anesthetized, spontaneously breathing rats: theoretical implications for mechanical ventilation.

OBJECTIVE: To test if hypothermia, induced by a sustained pentobarbital anesthesia, in rats can reduce ventilatory demands without compromising pulmonary gas-exchange efficiency. DESIGN: Prospective study. SETTING: Research laboratory in a hospital. SUBJECTS: One group of 11 female Sprague Dawley rats. INTERVENTIONS: The rats were anesthetized with 45 mg/kg pentobarbital, tracheostomized and intubated; their femoral veins and arteries were cannulated. After surgery, anesthesia and fluid balance were maintained (10 mg/kg per h pentobarbital, and 5 ml/kg per h saline, i.v.). Rectal temperature, mean arterial blood pressure (MAP), and heart rate (HR) were continuously monitored. The respiratory variables and gas-exchange profiles were determined at 38 degrees C (normothermia), and during stepwise hypothermia at 37, 35, 33, 31 and 29 degrees C. The arterial pressure of carbon dioxide (PaCO2), pH and arterial pressure of oxygen (PaO2) during hypothermia were corrected at body temperature. MEASUREMENTS AND RESULTS: Graded systemic hypothermia, with maintained anesthesia, produced a strong correlation between reduction in the respiratory frequency and rectal temperature (r2 = 0.55; p < 0.0001; n = 66). The minute volume was significantly reduced, starting at 35 degrees C, without significant changes in the tidal volume (repeated measures of analyses of variance followed by Dunnett multiple comparisons test). No significant changes occurred in the PaCO2, pH, PaO2, hemoglobin oxygen saturation, the calculated arterial oxygen content and estimated alveolar-arterial oxygen difference during mild hypothermia (37-33 degrees C). The PaO2, however, was significantly reduced below 31 degrees C. The MAP remained stable at different levels of hypothermia, whereas HR was significantly reduced below 33 degrees C. CONCLUSIONS: Mild hypothermia in rats, induced by a sustained pentobarbital anesthesia, reduces ventilation without compromising arterial oxygenation or acid-base balance, as measured at body temperature. Theoretically, our observations in spontaneously breathing rats imply that a combination of mild hypothermia with anesthesia could be safely utilized to maintain adequate ventilation, using relatively low minute ventilation. We speculate that such a maneuver, if applied during mechanical ventilation, may prevent secondary pulmonary damage by allowing the use of lower ventilator volume-pressure settings.

Hypoketonemia and age-related fasting hypoglycemia in growth hormone deficiency.

Body fuels were measured in 45 normal children and 17 growth hormone-deficient patients after 24 hours of fasting. After three months of therapy with human Growth Hormone (hGH) 16 of the patients were restudied. In all groups, beta-hydroxybutyrate (BOHB) concentrations correlated inversely with age and with glucose concentrations. When adjusted for these factors, the concentrations of BOHB were significantly lower in the growth hormone-deficient patients than in the control children, before (P less than 0.01) as well as after therapy (P less than 0.01). Only the five youngest patients became hypoglycemic. During fasting, ketones, which serve as an alternative fuel for the brain, spare glucose. Thus, a shortage of ketones would compromise the ability of the patient to conserve glucose and predispose the patient to fasting hypoglycemia. Accordingly, we propose that hypoketonemia is a critical factor in the genesis of fasting hypoglycemia in growth hormone deficiency.

Children with recently diagnosed diabetes: interactions within their families.

Cross-sectional findings drawn from the first year of a 4-year longitudinal study of preadolescent and early adolescent insulin-dependent diabetics and their families are presented. Using direct observation techniques and a specially designed coding system, the family interactions of 56 families with a recently diagnosed diabetic child are compared with those of 49 families with a child of similar age and sex, who has had a recent, serious acute illness. The two samples are contrasted in terms of each family member's (mother, father, and child) enabling and constraining interactions, controlling for social class differences. The findings reveal that the diabetic children and their parents expressed significantly more enabling (e.g., focusing, problem solving, active understanding) speeches than comparable members of the acute illness group. In addition, there are indications of particular constraining interactions (devaluing) occurring between fathers and diabetic children. Several alternative interpretations are offered to account for these results, together with plans for future research directions to investigate these hypothesized explanations.