Clinical features of patients with Kawasaki disease whose parents had the same disease

OBJECTIVE: To observe the clinical characteristics of patients with Kawasaki disease whose parent also had the same disorder. DESIGN: Cross-sectional study using the data from nationwide surveys of Kawasaki disease in Japan. SETTING: All hospitals with a bed capacity of 100 or more and pediatric departments in Japan. PATIENTS: All patients described on the 16th and 17th surveys covering the 4-year period from January 1, 1999, through December 31, 2002. MAIN OUTCOME MEASURES: We compared clinical details, including sibling case, recurrence, diagnosis, administration of intravenous immunoglobulin, and coronary abnormalities, between patients whose parents had Kawasaki disease and patients with no parental history of Kawasaki disease. We also observed age at onset and sex of affected parent-offspring pairs with Kawasaki disease confirmed by using the data of previous nationwide surveys. RESULTS: The odds for having sibling cases were significantly increased among patients whose parents also had Kawasaki disease (odds ratio, 6.94; 95% confidence interval, 2.77-17.38). Patients with parental Kawasaki disease were more likely to experience recurrent Kawasaki disease, receive additional administration of intravenous immunoglobulin, and experience coronary abnormalities at 1 month after onset. Among confirmed parent-offspring pairs with Kawasaki disease, the mean age at onset of offspring was younger than that of their parents (25.6 vs 41.8 months), despite the lack of statistical significance. CONCLUSIONS: Some cases of Kawasaki disease show familial susceptibility to the disorder. Family history, especially parental history of Kawasaki disease, may be an indicator of disease severity.     

Mortality among persons with a history of Kawasaki disease in Japan: Can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae?

Aim: To clarify the question of whether patients with Kawasaki disease suffer a higher mortality rate after the incidence of the disease in comparison with age-matched healthy individuals. Methods: Between July 1982 and December 1992, 52 collaborating hospitals collected data on all patients having a new, definite diagnosis of Kawasaki disease. Patients were followed up until 31 December 2001 or their death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. Results: Of 6576 patients enrolled, 29 (20 males and 9 females) died. The standardized mortality ratio (SMR: the observed number of deaths divided by the expected number of deaths based on the vital statistics in Japan) was 1.15 (95% CI: 0.77-1.66). In spite of the high SMRs during the acute phase, the mortality rate was not high after the acute phase for the entire group of patients. Although the SMR after the acute phase was 0.75 for those without cardiac sequelae, six males (but none of the females) with cardiac sequelae died during this period; and the SMR for the male group with cardiac sequelae was 1.95 (95% CI: 0.71-4.25). The mortality from congenital anomalies of the circulatory system was elevated, but no increase in cancer deaths was observed.

Conclusion: Although it was not statistically significant, the mortality rate among males with cardiac sequelae due to Kawasaki disease appeared to be higher than in the general population. On the other hand, the mortality rates for females with the sequelae and both males and females without sequelae were not elevated.     

Incidence rate of recurrent Kawasaki disease and related risk factors: from the results of nationwide surveys of Kawasaki disease in Japan

To investigate the incidence of recurrent Kawasaki disease, and to discuss some of the potential risk factors, data of the 13th and 14th nationwide surveys of Kawasaki disease in Japan were analyzed. To calculate the rate of recurrence, 10 679 patients with 31 501.9 person-years were observed. The mean observation period was 2.95 y. The rate of recurrence was 6.89 per 1000 person-years, with a high incidence within the 12 mo following the first episode. Conclusion: The incidence was high among those under 3 y of age and those with cardiac sequelae during the first episode. None of the other factors affected the incidence.     

Parents with a history of Kawasaki disease whose child also had the same disease

Background: The aim of this study was to describe time trends of prevalence and detailed characteristics of parents with a history of Kawasaki disease (KD) who had a child with the same disease using data from Japanese nationwide surveys on KD. Methods: Parents with a history of KD were identified using nationwide surveys of KD patients who visited hospitals between 1999 and 2008. To confirm KD histories, a parental questionnaire was sent to pediatricians who reported parental cases to the surveys for KD patients who visited hospitals from 2001 through 2004. Parental history was ascertained by merging data from the parental questionnaire with data from previous nationwide surveys, and detailed information about childhood KD was obtained from survey reports. Results: During the 10‐year study period, 407 parents with a child with KD were reported as having a KD history (0.43%). The prevalence of such parents significantly increased during this study period (regression coefficient: 0.13, 95% confidence interval: 0.05–0.20). Thirty‐one confirmed parents with the history were diagnosed between 1966 and 1984. All parents met the case definition of KD, and 33% had been treated with steroids. No parent with a KD history received intravenous immunoglobulin (IVIG). Conclusions: The prevalence of parents with KD history with a child with the same disease increased during the study period. Some of these parents had not been treated with IVIG because they were diagnosed before its use was widespread in Japan. An increase in the number of parents with the history is expected, thus continuous monitoring of familial cases with KD is required.     

Quality of care of the preterm infant--the parent and nurse perspective

Aim: To study the subjective opinions about what is important in care at neonatal units and child health centres (CHCs) for premature newborns, and to compare these opinions with the care actually given. Subjects: 21 mothers, 20 fathers and 15 nurses at the neonatal unit, and 21 mothers, 14 fathers and 18 nurses at CHCs. Methods: A questionnaire on quality of Care from the Patient's Perspective was used. It contained three dimensions: identity-oriented approach, medical-technical competence and socio-cultural atmosphere. Each dimension was evaluated in terms of subjective importance and perceived reality of given care. Results: In general, subjective importance was rated higher than perceived reality both for neonatal care and care at CHCs for the dimensions identity-oriented approach and medical-technical competence. However, higher ratings were given to neonatal care compared to CHCs for medical-technical competence. High-risk diagnoses and very low gestational age in the newborn did not affect the answers. Mothers rated medical-technical competence higher than nurses for neonatal care. Mothers and nurses rated identity-oriented approach higher than fathers for CHCs.

Conclusion: Although both neonatal care and care at CHCs were highly rated, improvements can be made to fulfil the expectations of parents and nurses. Neonatal units seem to be more efficient in taking care of the special needs of these newborns compared to CHCs. The need for an optimal identity-oriented approach, medical-technical competence and socio-cultural atmosphere could strengthen the possibilities of parents to be confident in their parental role.     

Case-control study of giant coronary aneurysms due to Kawasaki disease

BACKGROUND: Epidemiologic features of the formation of giant coronary aneurysm due to Kawasaki disease and its risk factors are not still clear. METHODS: One hundred and five patients with giant coronary aneurysms were selected from the 15th and 16th nationwide surveys of Kawasaki disease in Japan. With all other patients reported from the same hospital as a control group, odds ratios (OR) were calculated for some potential risk factors. RESULTS: Some factors affecting the formation of giant coronary aneurysms were revealed. Of these factors, the following were considered to be useful for the treatment of patients with Kawasaki disease: male sex (OR compared with females = 1.99), 0 years old (OR compared with 1-2 years = 1.71), visiting the hospital on 1-3 days of illness (OR compared to 4-6 days = 1.72), leukocyte count (OR with 1000 /mm3 increase = 0.56), neutrophil concentration among leukocyte (OR with 10% increase = 1.11), hemoglobin concentration (OR with 1 mg/dL increase = 0.73), alanine aminotransferase level (ALT; OR with 10 IU/dL increase = 1.02) and serum sodium level (OR with 1 mEq/L increase = 0.80). CONCLUSIONS: The observation of 105 cases with giant coronary aneurysms due to Kawasaki disease reported in the nationwide survey provides information about some risk factors and other considerations about the aneurysms.     

Risk factors associated with the need for additional intravenous gamma-globulin therapy for Kawasaki disease

Aim: To investigate the characteristics of patients with Kawasaki disease who needed intravenous gamma-globulin (IVGG) re-treatment. Methods: Using the database of the 17th nationwide survey in Japan, a total 11 366 patients were identified and analysed (1855 re-treatment patients and 9511 responders). Results: Multivariate logistic regression analysis showed that male sex (odds ratio (OR) 1.26; 95% CI 1.14-1.40), complete cases (OR 1.39; 95% CI 1.07-1.80), recurrence (OR 1.47; 95% CI 1.15-1.88), IVGG treatment within 4 d of illness (OR 2.05; 95% CI 1.84-2.27), daily dose of initial IVGG less than 1000 mg/Kg (OR 0.54; 95% CI 0.48-0.61), exanthema (OR 2.03; 95% CI 1.62-2.56), lips and oral lesions (OR 1.57; 95% CI 1.24-1.98), peripheral extremities changes (OR 1.85; 95% CI 1.54-2.22), and cervical lymphadenopathy (OR 1.89; 95% CI 1.66-2.16) were independent risk factors associated with the need for IVGG re-treatment.

Conclusion: Male sex, recurrence, and treatment with IVGG at a dose of 1000 mg/d or less within 4 d of illness onset are independent risk factors associated with the need for IVGG re-treatment.     

Relationship between problems related to child late effects and parent burnout after pediatric hematopoietic stem cell transplantation

A few studies have indicated that parents' reactions to a child's serious disease may entail long‐term stress for the parents. However, further knowledge of its consequences is valuable. The aim of the study was to investigate the occurrence of burnout in a Swedish national sample of parents of children who had undergone HSCT and survived. Burnout (Shirom–Melamed Burnout Questionnaire) and estimations of the child's health status (Lansky/Karnofsky estimations and study‐specific questions) were self‐reported by 159 mothers and 123 fathers. In addition, physicians made estimations of the child's health status (Lansky/Karnofsky estimations). Nonparametric tests revealed that burnout symptoms occurred more often among fathers of children who had undergone transplantation within the last five yr compared to fathers of children with no history of serious disease (34.4% vs. 19.9%). Burnout among mothers and fathers was associated with the child's number and severity of health impairments up to five yr after the child underwent HSCT (Spearman's rho for mothers 0.26–0.36 and for fathers 0.36–0.61). In conclusion, chronic stress in parents after a child's HSCT seems to abate eventually. However, parents should be monitored and offered adequate support when needed. Moreover, the situation of fathers in the often mother‐dominated pediatric setting should receive more attention in research as well as in the clinic.     

Mortality among persons with a history of Kawasaki disease in Japan: the fifth look

OBJECTIVE: To determine whether patients with Kawasaki disease have a higher death rate than an age-matched healthy population after disease occurrence. STUDY DESIGN: From July 1, 1982, to December 31, 1992, 52 collaborating hospitals collected data on all patients with a new definite diagnosis of Kawasaki disease. Patients were followed up until December 31, 1999, or death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. RESULTS: Of 6576 patients enrolled, 27 (19 male, 8 female) died. The standardized mortality ratio (the observed number of deaths divided by the expected number of deaths based on the vital statistics in Japan) was 1.25 (95% confidence interval, 0.84-1.85). Despite the high standardized mortality ratios during the acute disease phase, the mortality rate was not high after the acute phase for the entire group of patients. Although the standardized mortality ratio after the acute phase was 0.76 for those without cardiac sequelae, 6 male patients (no female patients) with cardiac sequelae died during this period, and the standardized mortality ratio for the male group with cardiac sequelae was 2.35 (95% confidence interval, 0.96-5.19). CONCLUSIONS: Although it was not statistically significant, the mortality rate among male patients with cardiac sequelae due to Kawasaki disease seemed higher than that in the general population. On the other hand, mortality rates for female patients with sequelae and both male and female patients without sequelae were not elevated.     

Giant coronary aneurysms due to Kawasaki disease: A case−control study

BACKGROUND: Epidemiologic features of giant coronary aneurysm due to Kawasaki disease and its risk factors are still not clear. METHODS: Sixty-six patients with giant coronary aneurysms were reported to a 15th nationwide survey of Kawasaki disease in Japan. With all other patients treated in the same hospital as a control group, odds ratios were calculated for certain potential risk factors. RESULTS: Infant males aged less than 1 year,neutrophil concentration among leukocyte, late administration of intravenous gammaglobulin (IVGG) therapy and additional administration of IVGGwere considered as risk factors of giant coronary aneurysms due to Kawasaki disease. In univariate analysis, use of IVGG therapy and a large amount of IVGG (2500+ mg/kg)elevated the risk, whereas the relationship disappeared after the adjustment. CONCLUSIONS: The observation of 66 cases with giant coronary aneurysms due to Kawasaki disease reported to the nationwide survey provides some risk factors and consideration about the aneurysms.     

Re-treatment regimens for acute stage of Kawasaki disease patients who failed to respond to initial intravenous immunoglobulin therapy: Analysis from the 17th nationwide survey

BACKGROUND: Current regimens for re-treatment of patients with Kawasaki disease who failed to respond to the initial intravenous immunoglobulin (IVIG) therapy are still uncertain. The purpose of this study is to reveal what regimens were used as the initial therapy and re-treatment for acute stage of Kawasaki disease in the current Japanese medical setting. METHODS: The 17th nationwide survey on Kawasaki disease covered patients whose onset was in 2001 and 2002. In questionnaires sent to all hospitals with a bed capacity of 100 or more and a pediatric department, several questions related to therapeutic regimens for Kawasaki disease were posed. The authors observed the proportions of hospitals that had regimens for patients who failed to respond to the initial therapy. RESULTS: Among those hospitals that responded to the survey, 1052 (64.1%) reported that at least one patient with Kawasaki disease visited the hospital. Among these 1052 hospitals, 73.3% had a regimen to administer 30-39 mg/kg per day of oral aspirin with initial IVIG. The proportion of hospitals that used 1 g/kg per day of IVIG for 2 days was the largest among the options for the initial treatment. For those patients who fail to respond to the initial therapy, 464 hospitals (44.1%) reported that their pediatricians would use additional IVIG only. The number of hospitals that planned to administer high-dose IVIG and ulinastatin was 185 (17.6%). The number of hospitals having regimens of additional IVIG and steroids was 54 (5.1%). CONCLUSIONS: The current status of the treatment for patients with Kawasaki disease not responding to the initial IVIG therapy in Japan was revealed. A randomized trial of a large sample is needed to ascertain the effectiveness of several options for re-treating Kawasaki disease.     

Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease

BACKGROUND: Although some laboratory findings are known to be indicators of the risk of giant coronary aneurysm formation among Kawasaki disease patients, an appropriate cut-off point to predict aneurysm formation is not clear. METHODS: One hundred and five patients with giant coronary aneurysms were selected from the 15th and 16th nationwide surveys of Kawasaki disease in Japan. A total of 2936 patients without Kawasaki disease were recruited from a single hospital as a control group. Odds ratios were calculated for six laboratory data with specific values as cut-off points. Receiver operating characteristic (ROC) curves were observed to determine the most appropriate laboratory tests and cut-off points. RESULTS: Hematocrit, leukocyte count, neutrophil proportion, and hemoglobin had one or more peaks of odds ratio for specific cut-off points, but they did not have a clear cut-off point for the predictor according to the receiver operating characteristic curves. Alanine aminotransferase (ALT) increased the risk of giant coronary aneurysms continuously so no clearly appropriate cut-off point was identified. Serum sodium concentration of 135 mEq/L had a peak of odds ratio, and those with <135 mEq/L had the highest odds ratio (4.78). This value seemed appropriate with a sensitivity of 78% and specificity of 57%, although the predictive positive value was as small as 5%. CONCLUSION: The author's propose that a serum sodium concentration of <135 mEq/L at the patient's first visit to hospital may be a predictor of giant coronary aneurysms due to Kawasaki disease.     

Increasing incidence of Kawasaki disease in Japan: Nationwide survey

Background: The last nationwide survey of Kawasaki disease in Japan was conducted in 2003; the epidemiologic features of the disease in Japan since then are unknown.
Methods: All the hospitals with a pediatric department and a bed capacity of ≥100, or hospitals having a bed capacity of <100 but specializing in pediatrics in Japan were asked to report (by mail) all patients with Kawasaki disease who visited the hospital due to the disease in 2003 and 2004.
Results: Of the 2335 hospitals asked to participate, 1058 reported 19 138 patients with Kawasaki disease during the 2 year period 2003–2004. The annual incidence in 2004 reached 174.0 per 100 000 children under 5 years of age. The yearly number of patients and annual incidence increased significantly after the last nationwide epidemic of the disease in 1986. The number of patients was largest in January and lowest in October. The age-specific incidence was highest for those aged 9–11 months, and 88.9% of the patients were under 5 years of age. Of the reported patients, 2595 (13.6%) had cardiac lesions in the acute phase of the disease and 844 (4.4%) had cardiac sequelae 1 month after the onset of the disease.
Conclusion: The number of patients and the incidence of Kawasaki disease in Japan has increased year by year in the last two decades.     

Introduction of food during the infant's first year: a study with emphasis on introduction of gluten and of egg, fish and peanut in allergy-risk families

Aim: The aim of the current study was to retrospectively examine introduction of food during the first year in a representative sample of Swedish children. A secondary aim was to study how parents with history of atopy introduced food to their infants. Methods: Data derive from 467 infants who visited child health centres in three different counties in Sweden for health check-up at 12 mo of age. The parents were asked to fill in a questionnaire about breastfeeding and/or formula feeding, time of introduction of weaning food focusing on cow's milk, follow-on formula, porridge, fish and egg. Questions regarding hypersensitivity in the family, peanut consumption of mother as well as in the child, and questions about number of siblings, ethnic background and parental education were included. Results: Compliance with suggested introduction of gluten-containing food was low; as many as 45% had avoided gluten until 6 mo of age, instead of introducing gluten between 4 and 6 mo. Only 33% of parents with stated family hypersensitivity avoided giving their child fish and 23% avoided egg during the first year, even though this recommendation was present at the time of the study. Almost 50% of all mothers had avoided peanuts during pregnancy even though there was no such advice. The avoidance of peanut was not connected to hypersensitivity in the family.

Conclusion: These results suggest that time of introduction of gluten was not in accordance with the current recommendation. The results imply that there is a need to follow up if and how this feeding information is distributed to parents with infants and also to sharpen the information to the right target groups, otherwise implementation of preventive strategies will be less useful.     

Fever of unknown origin in 185 paediatric patients: a single-centre experience

Aim: We conducted a prospective study to evaluate the causes and outcome in children with fever of unknown origin (FUO). Methods: From 1990 to 1999, 185 children with FUO were evaluated. Initial evaluation included routine haematological analysis, Epstein-Barr virus (EBV) serology, urine, stool or blood cultures, chest X-ray and tuberculin probe. Results: In 131 (70%) patients diagnosis was established, and 70 (37.8%) had infectious disease. EBV infection was the most common infection followed by visceral leishmaniasis (VL), urinary tract infection (UTI) and tuberculosis. Autoimmune disorders were diagnosed in 24 (12.9%), Kawasaki disease in 12 (6.4%), malignant diseases in 12 (6.4%) and miscellaneous conditions in 15 (8.1%) patients. In the remaining 54 (30%) patients, diagnosis was not established and most of them had self-limited disease. During the investigation, 26 (14%) patients developed serious organ dysfunction and five patients (two with virus-associated haemophagocytic syndrome, one with VL and two unknown) died.

Conclusion: The most important infectious causes of FUO in our study were EBV infection and VL. Kawasaki disease represented a significant cause of FUO at the beginning of our study because it was not recognized by primary-care physicians. We report myelodysplastic syndrome as another emerging cause of paediatric FUO. Repeated clinical examination and careful use of specific laboratory examinations, invasive diagnostic procedures or imaging are crucial in approaching paediatric FUO.     

Relationships between the children and the parents for coronary risk factors

BACKGROUND: We aimed to investigate the relation of coronary risk factors in children to coronary heart disease (CHD) or coronary risk factors in their parents. METHODS: A sample of 252 parents of 164 children with two or more coronary risk factors were included in this study. The control group consisted of 175 parents of 114 children with no risk factors. Both groups were evaluated for coronary risk factors and CHD. The children in the groups were separated into sex and age groups consisting of 7 to 11-years-olds, 12 to 15-years-old and 16 to 18-years-old. RESULTS: Many lipid parameters related with coronary risk factors in the mothers of 7 to 11-year-old girls, in the fathers of 7 to 11-year-old girls and 16 to 18-year-old boys were at higher levels than in the control group. Anthropometric parameters, especially those of reflecting body fatness such as skinfold thickness measurements and total bodyfat percentage values were at higher levels in the fathers of 12-15- and 16 to 18-year-old girls. The higher levels of most of the anthropometric and biochemical parameters in the fathers of 16 to 18-year-old boys were striking. Hyperlipidemia prevalences in the fathers of 7 to 11-year-old girls and boys were higher than the control parents. In the study group, the girls positively correlated with both their parents for total cholesterol levels and positively correlated with only their mothers for height, bodyfat percentage, triglycerides and low-density lipoprotein- cholesterol (LDL-C) levels. However, the boys positively correlated with their mothers for weight and with their fathers for bodyfat percentage, diastolic blood pressure (BP) values and serum LDL-C levels. The proportion of individuals who had ischemic findings on treadmill exercise testing was significantly greater than control group in only the fathers of 12 to 15-year-old boys (P<0.05). CONCLUSIONS: The parents, especially the fathers of children with coronary risk factors have higher levels of coronary risk factors than those in the control group. There is a familial aggregation of body fatness and adverse lipid levels in the families of the children with coronary risk factors. The parents of children recognized as having coronary risk factors should be evaluated for these risk factors too.     

The life situation of parents over the first year after their child's cancer diagnosis

Aim: To evaluate the impact of childhood cancer on the life of the parents. Method: A 1-y follow-up study, with two time points for questionnaires, was completed in 21 out of 26 eligible families, and there were 46 control families matched by mothers' educational status. Results: Half of the mothers worked outside home during the first year of their child's illness. The perceived amount of lost family income was high during the first few months. The attitudes of the parents were fairly positive as their family life and spouse relations were concerned. Feelings of being under strain or stressed were, by the mothers, described as intolerable in the beginning. However, standardized anxiety assessment failed to show an increase in feelings of anxiety. Own health was rated significantly negative by cancer parents.

Conclusions: Despite good family relationships, a need for supportive measures exists, especially during the first few months, and in-depth interviews by psychologists or special nurses might be a way of finding out possible anxiety. The perceived feelings of own health may also be an indicator of the level of distress. Parent support groups could also do more to offer opportunities of physical activities for the parents, not merely disease-related information and group discussions.     

Mortality among patients with a history of Kawasaki disease: The third look

Abstract Background: Long-term prognosis of Kawasaki disease is still unclear.
Methods: In a cohort study, 6576 patients with Kawasaki disease were observed from their first medical encounter because of the disease through the end of 1994, or until death. Standardized mortality ratios (SMR) with 95% confidence intervals (CI) were calculated with vital statistics data of Japan used for the control. Results: Of 6576 patients who met the eligibility criteria, 6550 (99.6%) were followed through either the end of the study or the date of death. Twenty patients (14 male, 6 female subjects) died during the study period; an overall SMR of 1.35 (95% CI 0.82–2.08) was calculated. The SMR was 1.45 (95% CI 0.79–2.44) for male subjects and 1.15 (95% CI 0.42–2.52) for female subjects. During the acute phase of the disease (the first 2 months after the first visit to hospital), the SMR was higher, particularly in male subjects (SMR 10.13, 95% CI 3.72–22.08). After the acute phase, however, both boys and girls had low SMR. Nine of the 20 deaths were caused by Kawasaki disease; there were three deaths as a result of congenital heart diseases and two subjects died of malignant neoplasms of lymphatic or hematopoietic tissues.
Conclusions: Although the mortality rate among those with a history of Kawasaki disease was elevated in Japan, many of the deaths that caused the elevation occurred during the acute phase of the disease. The mortality rate was not increased after the acute phase of the disease.     

Self-reported headache in schoolchildren: parents underestimate their children's headaches

Background: Most previous studies of childhood headache have used indirect parental/physician reports to estimate the prevalence of headache in children. Aim: To use direct information from children and to compare the results with data collected from parents. Study design/methods: A cross-sectional questionnaire was sent to parents of 7-12-y-olds in Oslo, Norway. The questionnaire included retrospective reports by the parents of the presence of headache among their children during the past 6 mo. A panel study was subsequently done with daily diaries completed by the children over 6 wk. This was done at school. Results: For 2126 children, both diary reports and parental reports were available. We found a 1-mo prevalence of self-reported headache of 57.6%. Parents, particularly fathers, reported lower headache prevalence than the children. The difference between parental reports and those of the children was larger when the child was a girl. There was a clear difference for the youngest children and parental underreporting for children with the most frequent headaches.

Conclusion: Since indirect parental reports of child headache underestimated headache frequency compared to direct diary-based self-reports, we suggest more widespread use of diary registration of headaches in studies of child headache.