Homocystinuria patient and caregiver survey: experiences of diagnosis and patient satisfaction.

BACKGROUND: The main genetic causes of homocystinuria are cystathionine beta-synthase (CBS) deficiency and the remethylation defects. Many patients present in childhood but milder forms may present later in life. Some countries have newborn screening programs for the homocystinurias but these do not detect all patients. RESULTS: HCU Network Australia is one of the very few support groups for patients with homocystinurias. Here we report the results of its survey of 143 patients and caregivers from 22 countries, evaluating current diagnostic pathways and management for the homocystinurias. Most (110) of the responses related to patients with CBS deficiency. The diagnosis was made by newborn screening in 20% of patients and in 50% of the others within 1 year of the initial symptom but in 12.5% it took over 15 years. The delay was attributed mainly to ignorance of the disease. Physicians need to learn to measure homocysteine concentrations in children with neurodevelopmental problems, and in patients with heterogeneous symptoms such as thromboembolism, dislocation of the optic lens, haemolytic uraemic syndrome, and psychiatric disease. Even when the diagnosis is made, the way it is communicated is sometimes poor. Early-onset CBS deficiency usually requires a low-protein diet with amino acid supplements. More than a third of the participants reported problems with the availability or cost of treatment. Only half of the patients always took their amino acid mixture. In contrast, good adherence to the protein restriction was reported in 98% but 80% said it was hard, time-consuming and caused unhappiness. CONCLUSIONS: There is often a long delay in diagnosing the homocystinurias unless this is achieved by newborn screening; this survey also highlights problems with the availability and cost of treatment and the palatability of protein substitutes.

Skin-related quality of life in children and adolescents with congenital melanocytic naevi - an analysis of self- and parent reports.

BACKGROUND: Congenital melanocytic naevi (CMN) may affect patient quality of life (QoL) due to medical complications (development of malignant melanoma or involvement of the central nervous system), skin-related discomfort or psychosocial sequelae. OBJECTIVES: To analyse skin-related QoL in children and adolescents with CMN and to identify predictors of low QoL. METHODS: Worldwide recruitment of participants through patient support groups. Data collection through a Web-based survey. QoL was assessed using the Children's Dermatology Life Quality Index© (CDLQI). Demographic and CMN-related characteristics were examined as possible predictors of impaired QoL. RESULTS: A total of 135 proxy reports for children affected by CMN aged 4-18 years (M = 9.34 years, SD = 4.16 years) and 28 self-reports of adolescents aged 14-18 years (M = 16.3 years, SD = 1.2 years) were included. The mean CDLQI score was 4.00 (SD = 4.39) for proxy reports and 6.89 (SD = 5.85) for self-reports. Most parents (76%) reported 'no' or a 'small' impact, 19% a 'moderate' and 5% a 'very large' or 'extremely large' impact on their child's QoL. In self-reports, 46% of the adolescents reported 'no' or a 'small impact', 43% a 'moderate' and 11% a 'very large' or 'extremely large' impact. Visible CMN location, malignant melanoma and higher child's age were important predictors of QoL impairments. CONCLUSIONS: Most CMN have a modest effect on QoL. However, there is large variability with a significant proportion of adolescents experiencing a moderate-to-large impact on QoL in contrast to children. Healthcare professionals should be aware of the predictors of QoL in children with CMN.

Posttraumatic stress and youth violence perpetration: A population-based cross-sectional study.

BACKGROUND: Exposure to trauma was found to increase later violent behaviours in youth but the underlying psychopathological mechanisms are unclear. This study aimed to test whether posttraumatic stress disorder (PTSD) is related to violent behaviours and whether PTSD symptoms mediate the relationship between the number of trauma experiences and violent behaviours in adolescents. METHOD: The present study is based on a nationally representative sample of 9th grade students with 3434 boys (mean age=15.5 years) and 3194 girls (mean age=15.5 years) in Switzerland. Lifetime exposure to traumatic events and current PTSD were assessed by the use of the University of California at Los Angeles Posttraumatic Stress Disorder Reaction Index (UCLA-RI). Logistic regression was used to assess associations between PTSD and violent behaviours, and structural equation modelling (SEM) was used to examine the meditation effects of PTSD. RESULTS: PTSD (boys: OR=7.9; girls: OR=5.5) was strongly related to violent behaviours. PTSD symptoms partially mediated the association between trauma exposure and violent behaviours in boys but not in girls. PTSD symptoms of dysphoric arousal were positively related to violent behaviours in both genders. Anxious arousal symptoms were negatively related to violent behaviours in boys but not in girls. CONCLUSIONS: In addition to trauma, posttraumatic stress is related to violent outcomes. However, specific symptom clusters of PTSD seem differently related to violent behaviours and they do not fully explain a trauma-violence link. Specific interventions to improve emotion regulation skills may be useful particularly in boys with elevated PTSD dysphoric arousal in order to break up the cycle of violence.

Quality of life in maltreated children and adult survivors of child maltreatment: a systematic review.

PURPOSE: To review data on health-related quality of life (HRQoL) in individuals with childhood trauma, including psychological maltreatment, physical maltreatment, sexual abuse, and neglect. METHODS: The literature search was conducted with pre-defined keywords using the following electronic bibliographic databases: EMBASE, PubMed, MEDLINE, CINAHL, PsyINFO, PSYNDEX, and Cochrane Database of Systematic Reviews. Further databases were searched for relevant dissertations. Study selection and data extraction were completed by two independent reviewers. RESULTS: The literature search yielded 1568 entries. Nineteen articles met all inclusion criteria and were retained for further analysis. Findings quite consistently showed significant negative associations between child maltreatment and both self- and proxy-rated HRQoL. Effect sizes range from small to large. Number of types of maltreatment and HRQoL were found to be negatively related. CONCLUSION: Data on HRQoL for maltreated children are still rare. Studies often investigate adult survivors of child maltreatment. Considering HRQoL in children and adolescents who suffered maltreatment would allow the planning of effective interventions and the evaluation of treatments to improve HRQoL of these children.

Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data.

BACKGROUND: The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine. METHODS: Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed. RESULTS: In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96% of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype- phenotype correlations evident. CONCLUSIONS: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.

Motor dysfunction and behavioural problems frequently coexist with congenital heart disease in school-age children.

AIM: Patients with congenital heart disease are at risk of neurodevelopmental deficits. Impairments in motor and behavioural function occur frequently, but no information is available concerning the coexistence of deficits in these two developmental domains. This study explored the occurrence of motor and behavioural deficits and their coexistence in children with surgically corrected congenital heart disease. METHODS: Outcome was assessed in 95 children with congenital heart disease who had undergone cardiopulmonary bypass surgery. Their mean age was 9.6 years (SD 2.5). Motor function was assessed with the Zurich Neuromotor Assessment and behaviour with the Strength and Difficulties Questionnaire. RESULTS: Children with congenital heart disease performed poorer in all motor domains compared with the reference population (all p ≤ 0.001). Behaviour was affected in the domains 'emotional symptoms' and 'hyperactivity/inattention' (both p < 0.01), and 54% of the children with motor abnormalities showed behavioural deficits. Children with coexistent abnormalities in behaviour and motor function had higher rates of remedial school services and therapeutic support. CONCLUSION: Children with congenital heart disease are at risk of long-term motor and behavioural problems, and there is a high rate of coexistence of problems in both domains. Early and longitudinal assessment of all developmental domains is necessary to provide adequate early support.

Exploring causal pathways of child behavior and maternal mental health in families with a child with congenital heart disease: a longitudinal study.

BACKGROUND: A congenital heart defect (CHD) can increase the risk of mental health problems in affected children and their parents. The extent to which risk factors for these problems are shared in families or are specific to the individual family member is unclear. METHOD: Prospective data from the Norwegian Mother and Child Cohort Study (MoBa; n = 93,009) were linked with a nationwide CHD registry, and 408 children with CHD were identified. Mothers' reports on child internalizing problems and their own distress were assessed by questionnaires at child ages 6, 18 and 36 months. A structural model was applied to distinguish between familial (shared) factors and individual-specific factors for mental health problems. RESULTS: CHD was a substantial risk factor for problems in children and their mothers at all time points. CHD contributed on average 31% and 39% to the variance in children's and mothers' problems respectively. Both shared familial and individual-specific factors unique to CHD families contributed to risk for mental health problems. Whereas individual-specific risk factors contributed to the stability of problems in mothers, the effect of these factors lasted only a short time in children. Mutual influences over time were found between the mother's and the child's mental health at 18 and 36 months. CONCLUSIONS: The burden of CHD in a child is shared between family members but is also specific to the individual. This study points to a need for both an individual and a family-based approach to provide psychological support to children with CHD and their parents.

Health-related quality of life in men with corrected hypospadias: an explorative study.

OBJECTIVE: The aim of the study was to evaluate health-related quality of life (HRQoL) of men with a corrected hypospadias in comparison to circumcised controls. Furthermore, determinants of HRQoL were examined. PATIENTS AND METHODS: In a cross-sectional study, HRQoL of 45 men with corrected hypospadias (mean age: 26.2 years +/- 5.1) was compared with a control group of 46 circumcised men (mean age: 25.5 years +/- 4.9). Participants answered three questionnaires: The Medical Outcomes Study Short Form-36 item questionnaire (SF-36), the International Index of Erectile Function (IIEF), and the Penile Perception Score (PPS). RESULTS: Physical and mental dimensions of HRQoL were not impaired among men with corrected hypospadias if compared to circumcised men. Neither socio-demographic and medical variables nor erectile function (EF) predicted HRQoL. However, a negative genital self-perception (PPS) and a lower orgasmic function (OF) were risk factors for an impaired mental HRQoL. CONCLUSIONS: Our data suggest that the HRQoL of adult hypospadias patients is comparable to that of circumcised men. However, patients should be supported in developing a positive genital self-perception, because poor genital self-perception correlated with an impaired mental HRQoL. Since studies with non-operated men suggest that some adapt well to their penile condition, further studies should also include non-operated hypospadias.

Self-perceived health status and mental health outcomes in young adults born with less than 1000 g.

AIM: To assess self-perceived health status and mental health outcomes of former extremely low-birth-weight (ELBW) infants at young adulthood compared with community norms and to analyse predictors of poor outcome. METHODS: Fifty-five ELBW adults, 18 men (33%), with median (range) gestational age of 28.7 (25.0-34.0) weeks and birth weight of 930 (680-990) grams, born in Switzerland, were included. They self-rated their health status and mental health at a mean (range) age of 23.3 (21.8-25.9) years. Health status was measured by the Medical Outcomes Study Short Form-36 questionnaire and mental health by the Brief Symptom Inventory. RESULTS: The mean scores for both outcome measures were in the normal range. However, the study group self-rated significantly higher physical health status and lower mental health status compared with the community norms, and scores for self-perceived mental health tended to be worse in the former. ELBW adults reported more problems in socio-emotional role functioning compared with the community norms. Female sex was associated with poorer and bronchopulmonary dysplasia with better mental health status. CONCLUSION: Health status and mental health of former ELBW adults were overall satisfying. However, the comparison with the community norms revealed differences, which may be important for parental and patient counselling and developing support strategies.

Increased number of activated T cells in lymphocyte subsets of maltreated children: data from a pilot study.

OBJECTIVE: Maltreatment in childhood has been related to enduring changes in the immune system of adults, such as increased cell-mediated immune response. PURPOSE: Due to the lack of data in children, this study examined lymphocyte subset numbers and distribution during youth. METHODS: In 27 cases of 42 healthy but maltreated children, fully participating at follow-up 1-3years after the intervention of child protection team, and 19 cases of previously matched controls, analysis of blood samples by fluorescent activated cell sorter was consented. RESULTS: With regard to age references, total lymphocyte counts were aberrant in maltreated children but not in controls. When compared to controls, the percentages and absolute numbers of activated (HLA-DR+) CD4+helper and CD8+cytotoxic T cells were significantly higher in maltreated children. CONCLUSIONS: According to the typical distribution of HLA-DR+cells we assumed an increased stimulated cell-mediated immune function in maltreated children.

Symptoms of communication and social impairment in toddlers with congenital heart defects.

BACKGROUND: With the advances in congenital cardiac surgery and medical management, mortality rates for congenital heart defects (CHD) have declined remarkably. As the number of CHD survivors have increased there is a growing focus on developmental morbidity. The objective of the current study is to compare symptoms of communication and social impairment in 18-month-old children with different severity of CHD with those of controls. METHOD: We linked prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health, with a nationwide medical CHD registry and identified 198 18-month-olds with CHD in a cohort of 47,692. Three groups of CHD were distinguished: mild/moderate (n= 122), severe (n= 54) and CHD with comorbidity (n= 22). Mothers reported on the child's communication and social skills by completing items from the Ages and Stages Questionnaire as part of the Norwegian Mother and Child Cohort Study. RESULTS: Children aged 18 months old with CHD differed significantly from controls in levels of symptoms of communication impairment (P≤ 0.0001) and social impairment (P≤ 0.0001). The largest differences were found in children with CHD and comorbidity. Children with severe CHD also showed higher levels of both symptoms of communication and social impairment. Children with mild/moderate CHD showed a small difference only in symptoms of communication impairment. CONCLUSION: Children with severe CHD and CHD with comorbidity show more symptoms of communication and social impairment compared with a large cohort at the age of 18 months. It is important to broaden the scope of inquiry to involve communication and social developmental domains.

Emotional reactivity in infants with congenital heart defects: findings from a large case-cohort study in Norway.

AIM: Advances in medical treatment in recent years have led to dramatically improved survival rates of children with severe congenital heart defects (CHD). However, very little is known about the psychological consequences for these children, particularly during and after the early period of invasive treatment. In this study, we investigated the extent to which the severity of the CHD affects the child's emotional reactivity at 6 months of age. METHOD: We linked prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health with a nationwide medical CHD registry and identified 212 infants with CHD in a cohort of 61 299 infants. Mothers reported on their child's emotional reactivity at age 6 months by means of a standardized questionnaire. RESULTS: Infants with severe to moderate CHD had 60% higher odds for severe emotional reactivity (cut-off at the 85 percentile) compared with healthy infants, after controlling for important maternal and child confounders. CONCLUSION: Our study is the first to show elevated emotional reactivity in children with moderate to severe CHD, suggesting a need for special parental attention to soothe their distress. Follow-up studies will show whether this emotional reactivity is transient or an early marker of continuing emotional or behavioural problems.

Is there an ideal age for hypospadias repair? A pilot study.

OBJECTIVE: To assess whether repairing hypospadias before or after 18 months affects psychological adjustment, health-related quality of life (HRQoL) and surgical outcome. PATIENTS AND METHODS: Seventy-seven boys aged 6-17 years were assigned to one of two groups, according to whether they had a hypospadias repair before or after the age of 18 months. The surgical outcome was assessed using the pediatric penile perception score by non-involved urologists. A psychologist interviewed the patients to assess HRQoL and gender-role behavior. The child's psychological adjustment was assessed with a questionnaire for parents. RESULTS: The surgical outcome and complication rate were not significantly different between groups. A covariance analysis of HRQoL, gender-role behavior and psychological adjustment as a function of age at the last operation with current age as covariant was performed, but differences did not reach significance. CONCLUSION: This study does not provide evidence to support recommendations concerning the ideal age for hypospadias repair. In the absence of evidence of a benefit of early surgery, anesthesia-related risk factors must be considered when operating in very early infancy. Large, prospective studies, measuring surgical and psychological outcome with similar instruments to those presented may reveal whether there is a true ideal age for hypospadias surgery.

[The psychosocial/-sexual development of boys with hypospadias]. / Die psychosoziale/-sexuelle Entwicklung von Knaben mit einer Hypospadie.

Boys with hypospadias can suffer from specific psychological stress as a result of genital surgery and a cosmetically and/or functionally impaired penis. During recent decades intensive efforts have been made to improve the surgical techniques; yet the psychosocial and psychosexual development of children and adolescents after hypospadias surgery has only rarely been investigated. While the results of the few studies are altogether very contradictory, they also indicate that hypospadias patients suffer from specific problems like a negative perception of genital appearance. Therefore, they should be offered long-term follow-ups and psychosocial support until they reach young adulthood. For future research, it is necessary to systematically investigate the boys' quality of life and development in methodologically sound studies.

Child and parental personality are associated with glycaemic control in Type 1 diabetes.

AIM: Little is known about the influence of the personality of the child and the personalities of the child's parents on glycaemic control in Type 1 diabetes. Our objective was to examine the extent to which glycaemic control is associated with the child's and the parents' stable personality traits, using the Big Five personality model as the basic framework. METHODS: Participants were 64 children (aged 6-16 years) with recent-onset Type 1 diabetes and their parents. Glycaemic control (HbA(1c)) was assessed at 6 months, 1 year and 2 years after diagnosis; personality was assessed at 4-6 weeks, 6 months and 1 year after diagnosis. Associations of personality with mean HbA(1c) over 2 years were examined. RESULTS: Children with better glycaemic control had a personality pattern of high Agreeableness, high Conscientiousness and low Neuroticism. Mothers of children with better glycaemic control showed a similar personality pattern, whereas the personality of the father was only marginally related to glycaemic control. Children's Conscientiousness and mothers' Agreeableness together predicted 18% of the variability in mean HbA(1c). All associations were unchanged when we controlled for child's age. CONCLUSIONS: Glycaemic control in the child was associated with the same child and maternal personality characteristics that influence treatment adherence, health-promoting behaviours and general adjustment in adult populations. In future, studies are needed to examine attitudinal and behavioural mediators of this relationship. It is suggested that attention to the personalities of the child and the mother can help to tailor diabetes education to the individual child.

Outcome of medulloblastoma in children: long-term complications and quality of life.

To study the outcomes in long-term survivors of paediatric medulloblastoma (MB), we followed 51 consecutive children who were treated between 1980 and 2000 in a single institution. In 18 of 26 survivors (mean follow-up time 12.2 years), tumour control, neurological, endocrine, and neurocognitive complications and their impact on behavioural and psychological adjustment, and health-related quality of life (QoL) were comprehensively assessed using qualitative and quantitative measures. Endocrine deficits occurred in 61 %, neurological complications in 72 %, and significant school problems in 72 %. All patients had significant deficits in neurocognitive functioning: attention and processing speed was impaired in 79 %, learning and memory in 88 %, language in 56 %, visual perception in 50 %, and executive functions in 64 %. In comparison with healthy controls, social functioning was rated by the patients as the QoL dimension most affected. Parents' ratings were considerably lower than those of the patients. No MB survivor > 18 years of age (n = 12) had a boy- or girlfriend. Because of their treatment, including craniospinal radiotherapy, MB long-time survivors are not only at great risk for neurological, endocrine, and neurocognitive complications, but also of social isolation thereby decreasing self-rated QoL substantially.

Sagittal craniosynostosis: cognitive development, behaviour, and quality of life in unoperated children.

30 patients (23 m/7 f) with untreated, isolated sagittal craniosynostosis (ISC) were re-evaluated at an average age of 9.25 years (2.5 - 25.5). Assessed were neurological status, head shape, school performance, behaviour (with Child Behavior Checklist CBCL), quality of life (TACQOL questionnaire), and a detailed neuropsychological testing (30 patients, 17 siblings as controls). Almost all patients/parents were pleased with the current situation. The aesthetic appearance seemed less obvious compared to photos in infancy. Psychological adjustment as measured by the CBCL was well within normal range. There was a slight tendency for increased internalizing symptoms. TACQOL revealed a lower score for positive emotions. Total score and subscores of test batteries assessing general intellectual performance were in the average range. 6 patients had below average scores in subtests for learning and memory. 12 children had below average scores in one or more subtests for attention. These "deficits" were obviously not of functional importance as all children attended regular school classes (1 exception, an immigrant child of low socio-economic status). These reassuring results regarding school performances, behaviour, and quality of life as well as aesthetic outcome may be helpful when discussing the indication for surgical correction of ISC.

Predictors of coping strategy selection in paediatric patients.

AIM: To assess the prevalence of specific coping strategies and predictors of coping strategy selection in 179 patients (mean age = 10.2 y). The children were investigated one month after the occurrence of an accident (n = 105), diagnosis of cancer (n = 26) or diagnosis of diabetes mellitus type I (n = 48). RESULTS: Patients used a great variety of coping strategies. The most frequent strategies were cognitive avoidance, positive cognitive restructuring and avoidant actions. The strategies of seeking problem-focused support and emotion-focused support were rarely used. Diagnostic category, length of hospital stay, and gender were not associated with coping strategy use. Age, socioeconomic status and functional status of the patient were found to predict coping strategy selection. Younger children made less use of active coping, distraction and seeking support. Patients of lower socioeconomic status used religious coping strategies significantly more often, whereas patients with lower functional status used avoidance and support-seeking strategies more often. CONCLUSION: In this study it was found that paediatric patients used a wide variety of coping strategies, irrespective of diagnosis and gender. Age of the child and functional status were the most important predictors of coping strategy selection.

Does cartoon movie distraction decrease burned children's pain behavior?

The purpose of this study was to evaluate cartoon movie viewing as a practical and low-cost intervention to decrease burned children's pain behavior during dressing changes. Thirteen children, 4 to 12 years of age, with a mean TBSA burn of 7.9% were assessed using a reversal, single-subject experimental design. The experimental condition consisted of the presentation of a cartoon movie as a nonpharmacologic intervention in conjunction with a standardized analgesic medication. In the control condition children's pain was treated with the standardized analgesic medication only. Behavioral distress was measured during the first six dressing changes postburn with the Observational Scale of Behavioral Distress. No significant effect of cartoon movie distraction on observed behavioral distress in patients was found. Interrater reliability of the Observational Scale of Behavioral Distress was good (kappa =.87-.98). Wound debridement was found to be the most painful part of the dressing change. A simple, easily applicable, and low-cost distraction intervention such as presenting cartoon movies does not seem to be sufficiently powerful to measurably reduce burned children's distress during dressing changes. Findings are based on purely observational data. Inclusion of self-report measures in future studies might reveal intervention effects on anxiety and subjective pain perception.

Living anonymous kidney donation: what does the public think?

BACKGROUND: Health professionals are increasingly turning to living organ donation to augment cadaveric donation. Although living donation is currently performed with donors who are either genetically or emotionally related to the recipient, a 1997 British Columbia Transplant Society survey indicated that 32% of BC residents would be willing to donate a kidney, while alive, to a stranger (unpublished data). The goal of this study is to tap the public pulse about the living anonymous donor (LAD) by replicating and expanding the 1997 findings. METHODS: Five hundred BC residents completed a telephone survey including demographic information, questions about their organ donation behaviors and attitudes, and their willingness to donate a kidney, while alive, to particular individuals (child, spouse, parent, relative, friend, and stranger). To improve the methodological rigor of the 1997 study, an informed condition was added in the current study where participants learned about living donation before being asked about their willingness to donate. RESULTS: There were no differences among the 1997 results and the two conditions in the 2000 survey. Twenty-eight percent of participants in the uninformed condition and 29% of participants in the informed condition indicated that they would be willing to be LADs. LADs were more likely than self-reported non-donors to have registered as cadaveric donors and to endorse attitudes that were congruent with wanting to donate to a stranger. CONCLUSIONS: This study replicates the 1997 findings and increases confidence that a significant minority of British Columbians support living anonymous donation and that some would consider becoming LADs themselves.