Quality Of Life In Boys Research Articles

The impact of clinical trial participation on quality of life and psychosocial well-being in children with Duchenne muscular dystrophy and their parents

Clinical trials provide Duchenne muscular dystrophy (DMD) patients access to medication. Nevertheless, such involvement can impose certain burdens, as the protocol may entail strict adherence and additional demands. This study assessed the psychosocial functioning and quality of life in boys with DMD and their parents who participate in clinical trials. DMD families participating in clinical trials (n = 25) and families with DMD patients not involved in clinical trials (N = 18) were included. Questionnaires assessing psychosocial well-being and quality of life were completed by the participants and their parents. MANOVAs were employed to compare outcomes between groups. The results showed that mothers in the clinical trial group experienced significantly higher scores of somatic complaints. Fathers in the clinical trial group reported significantly fewer psychological issues compared to fathers from the other group. DMD patients participating in clinical trials reported a better overall and emotional quality of life compared to them not involved in clinical trials. This study suggests that clinical trial participation may have positive effects on quality of life and psychosocial outcomes. It highlights the importance of providing support and counseling throughout the clinical trial decision making process to minimize potential burden for both eligible and ineligible patients.

Distinct developmental trajectories of health-related quality of life for boys and girls throughout childhood and adolescence; a national level longitudinal study

BackgroundTo identify and describe distinct developmental trajectories of health-related quality of life (HRQoL) in a national level Australian population sample, overall and separately for boys and girls.MethodsData were from the Longitudinal Study of Australian Children (LSAC). Participants were children aged 4–5 years recruited in 2004 and followed through to age 16–17 years in 2016, and their caregivers. Group-based trajectory modelling was used to identify groups of children that follow qualitatively distinct developmental trajectories of HRQoL.ResultsThree distinct trajectories were identified for the total sample: (1) high-stable (52.2% of children); (2) middle-stable (38.0%); and (3) low-declining (9.8%). These trajectories differed for boys, who saw increasing HRQoL in the highest trajectory group; a middle-stable trajectory; and declining and rebounding HRQoL in the lowest trajectory group. In contrast, girls saw no increasing or rebounding trajectories; approximately half of girls had high-stable HRQoL and the remaining half had either steadily or rapidly declining HRQoL from age 4–5 to 16–17 years.ConclusionsOur results highlight the importance of considering the distinct trajectories for girls and boys and not relying on population mean levels of HRQoL for decision-making. The presence of developmentally distinct trajectories of HRQoL, and differences in the trajectories faced by boys and girls, should be considered when assessing the effectiveness of treatments and interventions impacting upon HRQoL throughout childhood and adolescence. Failure to account for these pre-existing trajectories may over- or under-estimate treatment effects.

What's missing in sex chromosome aneuploidies? Representation and inclusion

What's missing in sex chromosome aneuploidies? Representation and inclusion

Health Promotion through Movement Behaviors and Its Relationship with Quality of Life in Spanish High School Adolescents: A Predictive Study

A growing number of studies have highlighted the health benefits of high physical activity, low screen time, and optimal sleep duration among school-age children and adolescents. Objective: The present study proposes to examine the individual and combined association between movement behaviors (physical activity, screen time, and sleep time) and quality of life in boys and girls. Method: A total of 319 Spanish primary and secondary school students participated in the study. Physical activity, screen time, sleep duration, and quality of life were evaluated. Results: Descriptive, correlation, and regression analyses were carried out in order to improve knowledge about health-related behaviors for all participants. The results found significant positive associations between physical activities and sleep time with quality of life. Finally, the regression models showed that physical activity scores predict quality of life, especially in children. It is concluded that movement behaviors are important in association with quality of life. Likewise, the impact of physical activity on the quality of life is highlighted as the main behavior in the prediction of the quality of life for a population of school adolescents.

Updating the Canadian Hemophilia Outcomes–Kids’ Life Assessment Tool (CHO‐KLAT) in the era of extended half‐life clotting factor concentrates

IntroductionThe purpose of this study was to review and update the content of the Canadian Hemophilia Outcomes–Kids’ Life Assessment Tool version 2.0 (CHO‐KLAT), in the context of extended half‐life (EHL) factor concentrates (FCs) and to establish the validity and reliability of the updated CHO‐KLAT. MethodsFocus groups were conducted with boys with hemophilia, their parents, and health care providers across Canada to review the CHO‐KLAT v2.0 and determine if any modifications were required. The validity of the revised CHO‐KLAT (version 3.0) was then determined in a sample of boys with hemophilia and their parents by calculating its correlation with the Pediatric Quality of Life Core Module (PedsQL‐Core). Test‐retest reliability was assessed using an intraclass correlation coefficient (ICC). ResultsThirteen focus groups at 5 pediatric hemophilia treatment centers (HTCs) (n = 71) resulted in 19 changes to the CHO‐KLAT v2.0, generating a revised 40‐item CHO‐KLAT, the CHO‐KLAT v3.0. Thirty‐five boys with hemophilia (median age, 14; range, 7–17 years) and 47 parents participated in the validation of the CHO‐KLAT v3.0. There was a moderate correlation between the CHO‐KLAT v3.0 child self‐report and PedsQL‐Core (r = 0.56, P = .01), and a strong correlation between the CHO‐KLAT v3.0 parent‐proxy and PedsQL‐Core (r = .79, P = .0007). The test‐retest reliability ICC was 0.90 for the child self‐report CHO‐KLAT v3.0 and 0.68 for the parent‐proxy CHO‐KLAT v3.0. ConclusionThe CHO‐KLAT v3.0 is a reliable and valid child‐centric tool that effectively measures health‐related quality of life in boys with hemophilia who are receiving standard half‐life or EHL FCs.

Testis Sparing Surgery in Pediatric Testicular Tumors.

Simple SummaryTestis sparing surgery (TSS) is a safe treatment option in selected cases of testicular tumors in adults, focusing on technical feasibility, oncologic safety, preserving of testicular function, and long-term outcome. This surgical technique is also increasingly being considered in children, as benign tumors are more common in this population. With this systematic review, we aim to evaluate outcome of TSS and to investigate under which circumstances TSS can be considered safe in boys with testicular tumors. Based on the current practice described in this systematic review, combined with the outcome of TSS, we would like to suggest an algorithm to guide clinicians in determining the appropriate surgical treatment in prepubertal patients less than 12 years of age with a testicular tumor. TSS may lead to improved testicular function and quality of life in boys with testicular tumors. Objective: The purpose of this review is to evaluate the outcomes of testis sparing surgery (TSS) and to investigate under which circumstances TSS can be considered a safe treatment option in pediatric patients with testicular tumors. Methods: A database search was performed in Cochrane, Pubmed, and Embase for studies that focused on TSS as treatment for testicular tumors in the pediatric population, excluding reviews and single case reports. Results: Twenty studies, describing the surgical treatment of 777 patients with testicular tumors, were included in the analysis. The majority of pediatric patients with benign germ cell tumors (GCTs) (mean age: 3.7 years) and sex cord-stromal tumors (SCSTs) (mean age: 6.6 years) were treated with TSS, 61.9% and 61.2%, respectively. No cases of testicular atrophy occurred. Four of the benign GCTs, i.e., three teratomas and one epidermoid cyst, recurred. No cases of recurrence were reported in patients with SCSTs. Of the 243 malignant GCTs (mean age: 4.2 years), only one patient had TSS (0.4%). Conclusion: TSS is a safe treatment option for prepubertal patients less than 12 years of age with benign GCTs and low grade SCSTs.

Effect of Testosterone Treatment for Delayed Puberty in Duchenne Muscular Dystrophy

Objective: To evaluate the impact of pubertal induction with testosterone on bone health, body composition, and motor function in boys with Duchenne muscular dystrophy (DMD) receiving long-term glucocorticoid. Study Design: A retrospective, observational, pre-post study investigating the impact of testosterone therapy on bone mass accrual, vertebral fracture incidence, body composition, motor function, and quality of life in boys with DMD. All those boys aged ≥14 years, on chronic steroid therapy, who had delayed puberty, and were receiving oral testosterone or oral and then transitioned to intramuscular testosterone, to complete virilization, were included. Prior/concomitant zoledronic acid use was included. The primary outcome was lumbar spine areal bone mineral density (BMD LS). Results: Puberty was induced, using oral testosterone undecanoate in 16 individuals, 10 of whom had transited to intramuscular testosterone at time of assessment. Median age at testosterone onset was 14.5 years (range 14–17.7). Median duration of testosterone therapy was 2.5 years (range 1.0–4.5). There was statistically significant increase in median BMD LS (0.523–0.700, p < 0.001) and median annualized percentage change of BMD LS (–1.34 to +10.08%, p < 0.001), with median Tanner stage 4 at evaluation (range 2–4). Ten of 14 assessed had no progression in vertebral fractures. Fat mass index (FMI) standard deviation score (SDS), lean body mass index (LBMI) SDS, and percentage change of FMI and LBMI were statistically unchanged. Cardiac function remained stable. Motor function in non-ambulatory individuals with Egen Klassifikation scores improved in 7 of 8. Conclusion: Testosterone for delayed puberty acted as an adjunct to bisphosphonates to increase bone density and stabilize vertebral fracture in most boys with DMD.

The Relationship Between Maternal Stress and Boys' ADHD Symptoms and Quality of Life: An Australian Prospective Cohort Study

PurposeThis study prospectively examined the role of maternal stress in boys' attention deficit hyperactivity disorder (ADHD) symptoms and quality of life (QoL). MethodsChildren with ADHD (5–13 years) were recruited from 21 pediatric practices and followed up 12 months later (n = 166). Maternal stress was examined at baseline, and boys' ADHD symptoms and QoL were examined at baseline and 12 months later. Linear regressions examined whether baseline maternal stress predicted child ADHD symptoms and QoL 12 months later in a series of adjusted models that accounted for child age, ADHD medication use, neighborhood disadvantage, comorbidities and baseline ADHD symptoms or QoL (full model). ResultsIn the unadjusted model, maternal stress at baseline was significantly associated with more severe parent-reported ADHD symptoms at 12 months, accounting for 5.7% of the variance in ADHD symptoms, but this association was attenuated after adjustments in the full model. Baseline maternal stress was associated with poorer QoL at 12 months in boys in the unadjusted model, accounting for 12.4% of the variance, which remained significant in the full adjusted model. ConclusionsMaternal stress is associated with lowered QoL in boys, and may pose a risk for boys' later QoL. Practice implicationsStress management interventions with mothers of children with ADHD experiencing heightened stress are warranted, and are likely to have a positive impact on mothers as well as children.

Predictors of Health-Related Quality of Life in boys with Duchenne muscular dystrophy from six European countries.

Duchenne muscular dystrophy (DMD) is a progressive, genetically determined neuromuscular disease that affects males and leads to severe physical disability in early teenage years. Over the last decades, patient-reported outcomes such as Health-Related Quality of Life (HRQoL) gained great interest in clinical research. However, little is known about factors affecting HRQoL in boys with DMD. Data from the multi-center CARE-NMD project of boys with DMD from six European countries collected between 2011 and 2012 were analyzed (8-17years old; n=321). HRQoL was measured using the KIDSCREEN-10 index, the Pediatric Quality of Life Inventory (PedsQL) and the Neuromuscular Module of the PedsQL (NMM). Linear regression models served to examine influences of socio-demographic, disease- and treatment-specific as well as participation- and environment-related factors on overall and disease-specific HRQoL. Proportions of explained variance varied across models using different outcomes (18-34%). Overall HRQoL according to the KIDSCREEN-10 index was associated with household income, the frequency of attending a clinic with specialized staff, the number of days spent outside home, and the attitude of the local community, but no significant association with age occurred. Overall HRQoL according to the generic PedsQL and disease-specific HRQoL were both positively associated with age and influenced by the country of residence, the disease stage, number of days spent outside home, and the attitude of the local community. Our results may be relevant for clinical practice and planning interventions for this population, but should be confirmed by future research. Further questions for future studies on boys with DMD are proposed.

PUBLIC POLICY, CHILD DEVELOPMENT RESEARCH AND BOYS AT RISK: CHALLENGING, ENDURING AND NECESSARY PARTNERSHIP.

Research findings documenting the issues and challenges of boys prebirth through age 5 years have barely penetrated the arena of public policy making nor has it permeated the public agenda of politicians, government, or other funding stakeholders. The purpose of this article is to articulate pathways for researchers to enter into the policy-making process. We review critical issues related to implementing the process of public policy. We argue that the policy process needs to be informed by more dynamic theoretical models of human development, and that researchers and clinicians need to be exposed more deeply to the processes required to inform and subsequently change public policy. We contend that most quantitative research on boys at risk occurs at the micro- and the mesosystem level rather than at the exo- and the macrosystem levels where structural societal policies embedded in economic and racial inequities contribute to risk. Researchers, clinicians, and policy makers need to create collaborative partnerships designed to develop, advocate, and implement more evidence-based policies designed to enhance the quality of life for boys at risk.

Dairy Food Consumption and Health-Related Quality of Life in Boys: Preliminary Findings from a 5-Year Cohort Study

Objectives: There are few reported data on the relationship between dairy food consumption and health-related quality of life (QOL). In this cohort study, we aimed to assess the association between dairy food intake and QOL scores during adolescence. Methods: Of the 1216 participants who were followed up over 5 years (i.e., from age 12 to 17), 858 participants had complete data on dietary intakes and information on QOL scores at the 5-year survey. Dairy consumption was assessed from validated semiquantitative food frequency questionnaires. Health-related QOL was assessed by the Pediatric Quality of Life Inventory (PedsQL). Results: Among adolescent boys, after multivariable adjustment, those in the highest tertile of yogurt consumption compared to those in the lowest tertile of consumption had 4.7, 5.9, and 9.1 units higher for total score (p-trend = 0.03), and psychosocial health summary (p-trend = 0.02), and school functioning scores (p-trend = 0.01). Boys who remained in the highest tertile compared to the lowest tertile of yogurt consumption during adolescence from ages 12 to 17 had 7.4 and 12.4 units higher psychosocial health summary (p-trend = 0.04) and school functioning scores (p-trend = 0.02), respectively. Nonsignificant associations were observed among girls and with total dairy intake and milk and cheese consumption. Conclusions: Yogurt consumption in boys could influence health-related QOL scores. Given that ours is an observational study we cannot establish a causal nature and direction of the relationship between yogurt intake and quality of life, our findings require further confirmation and clarification by other studies.

The quality of life in boys with Duchenne muscular dystrophy

We conducted a study to evaluate the quality of life in boys with Duchenne muscular dystrophy aged 8–18 years, compared with that in matched healthy controls. A total of 85 boys with Duchenne muscular dystrophy aged 8–18 years and 136 age, sex and living place matched healthy controls were included in this study. Patients and one of their parents separately completed the 27-item Persian version of KIDSCREEN questionnaire (child and adolescent version and parent version). From the children's perspective, the quality of life in patients was found to be lower in two subclasses: “physical activities and health” (p < 0.001) and “friends” (p = 0.005). Parental estimation of their sick child's quality of life was significantly lower than children's own assessment in two subclasses: “physical activities and health” (p < 0.001) and “general mood and feelings” (p < 0.001). Our results indicate that boys with Duchenne muscular dystrophy have quite a satisfactory quality of life. A happier and more hopeful life can be promoted through increasing social support and improving the parental knowledge regarding their child's more positive life perspective.

Multimodal Therapy Involving High-Intensity Interval Training Improves the Physical Fitness, Motor Skills, Social Behavior, and Quality of Life of Boys With ADHD: A Randomized Controlled Study

Objective: To compare the effects of multimodal therapy including supervised high-intensity interval training (HIIT) with those of standard multimodal therapy (TRAD) concerning key variables of physical fitness (peak power and oxygen uptake), motor skills, social behavior, and quality of life in boys with ADHD. Method: A single-center, two-arm randomized, controlled design was used, with 28 boys (8-13 years of age, IQ = 83-136) being randomly assigned to multimodal HIIT (three sessions/week, 4 × 4-min intervals at 95% of peak heart rate) or TRAD. The Movement Assessment Battery for Children II evaluated motor skills and the German version of the hyperkinetic disorder questionnaire for external evaluation by the guardians (FBB-HKS) or German version of the hyperkinetic disorder questionnaire for self-assessment by the children (SBB-HKS) and the KINDL-R questionnaires mental health and health-related quality of life. Results: Both interventions enhanced peak power, and HIIT also reduced submaximal oxygen uptake. HIIT was more effective than TRAD in improving the total score for motor skills (including manual dexterity and ball skills; p < .05), self-esteem, friends, and competence (p < .05) and, moreover, improved subjective ratings of attention. Conclusion: Three weeks of multimodal therapy including HIIT improved physical fitness, motor skills, certain aspects of quality of life, competence, and attention in boys with ADHD.

Trends With Corticosteroid Use in Males With Duchenne Muscular Dystrophy Born 1982-2001

This study examines trends in corticosteroid use for males with Duchenne muscular dystrophy by birth year, race/ethnicity, and knowledge of Duchenne muscular dystrophy family history. Firstborn males (n = 521) selected from a population-based surveillance system of Duchenne muscular dystrophy were analyzed using Kaplan Meier and regression methods. Comparing males born 1982 to 1986 with males born 1997 to 2001, steroid use increased from 54% to 72% and mean age at steroid initiation decreased from 8.2 to 7.1 years. Hispanics and non-Hispanic Black males used steroids less frequently and delayed initiation compared to white males. Compared to males without a Duchenne muscular dystrophy family history, males with known family history were half as likely to use steroids. Duration of steroid use increased over time and age at initiation decreased. Racial/ethnic disparities exist for steroid use and should be addressed to improve outcome and quality of life for boys with Duchenne muscular dystrophy.

The level of agreement between child self-reports and parent proxy-reports of health-related quality of life in boys with Duchenne muscular dystrophy

To investigate the level of agreement between child self-reports and parent proxy-reports of the health-related quality of life (HRQoL) in boys with Duchenne muscular dystrophy (DMD) using both classical test theory (CTT) and Rasch analysis. A total of 63 boys with DMD and their parents completed the pediatric quality of life inventory version 4.0 child self-report and parent proxy-report of HRQoL, respectively. The data were analyzed using both the CTT (scale-score level) and Rasch analysis (item-level). The intraclass correlation coefficient (ICC, scale-score level) between children and parents showed good to moderate agreement, although parents consistently underestimated their child HRQoL. In Rasch analysis (item-level), 1 out of 8 items was significantly different between children and parents in the physical health scale. Also, 3 out of 15 items were significantly different between those two groups in the psychosocial health scale. By applying both scale-score and item-level analyses, our study seeks to broaden the understanding of the discrepancy of the ratings between child self-reports and parent proxy-reports. The findings could provide further information about the decision-making process when selecting therapy and care programs.

P.11.8 The impact of deflazacort on upper extremity function in young adults with Duchenne muscular dystrophy

Corticosteroid treatment has significantly delayed the progression of Duchenne muscular dystrophy (DMD). Once wheelchair dependent, the adolescent relies on upper extremity (UE) function for activities of daily living including feeding, wheelchair mobility, transfers and recreation. The loss of independent feeding is a major milestone and an adjustment for both the boys and their parents. The Brooke Scale is a quick and effective tool for clinical practice that provides a classification of UE function. Grade 1 or 2 indicates shoulder strength to elevate their arms above their head. Grade 3 or 4 indicates they can flex at their elbow and feed independently. Grade 5 or 6 indicates they can not feed independently. We present a prospective cohort of 39 males, older than 15 yrs, with DMD, followed at Holland Bloorview Kids Rehabilitation Hospital in Toronto. All boys were treated with daily deflazacort since 7.7 ± 1.6 yrs. The mean dose of deflazacort was 35 ± 3 mg (range 24–42 mg). The mean age at last follow-up was 19.2 ± 3.2 yrs (range 15– 26 yrs). At 16 yrs, 65% were non-ambulatory, by 18 yrs 94% were non-ambulatory and by 22 yrs all patients were non-ambulatory. None had spinal surgery. The Brooke Scale was 1 ± 0 at 8 yrs, 1.0 ± 0.2 at 10 yrs, 1.2 ± 0.4 at 12 yrs, 1.6 ± 0.8 at 14 yrs, 1.9 ± 0.9 at 16 yrs, 2.9 ± 0.9 at 18 yrs, 2.8 ± 0.8 at 20 yrs and 3.0 ± 1.0 at 22 yrs of age. At 18 yrs, 96% (27/28) were able to eat independently and at 22 yrs 100% (9/9) were able to eat independently. In corticosteroid naive boys, Steffensen et al. (2002) describe that boys at 15 yrs had a median Brooke Scale of 5 (range 2–5) and by 20 yrs had a median Brook scale of 5 (range 5–6). Rahbek et al. (2005) describes that boys at 18 yrs could not feed themselves but could operate an electric wheelchair. Deflazacort treatment has significantly maintained UE strength and preserved independence for eating well into their third decade resulting in a significant impact on quality of life for boys and parents.

Molecular Therapeutic Strategies Targeting Duchenne Muscular Dystrophy

Since the discovery of the gene for Duchenne muscular dystrophy more than 20 years ago, scientists have worked to apply molecular principles for restoration of the dystrophin protein and correction of the underlying physiologic defect that predisposes muscle fibers to injury. Recent studies provide realistic hope that molecular therapies may help patients who have this disorder. At present, only corticosteroids can improve walking ability and increase quality of life for boys with this disease. The results are modest and encumbered by side effects. The authors review 3 molecular therapeutic approaches that have been introduced into the clinic: (1) gene replacement therapy, (2) mutation suppression, and (3) exon skipping.

Health-related Quality of Life in Boys With Duchenne Muscular Dystrophy: Agreement Between Parents and Their Sons

This study investigated agreement between boys and their parents when reporting on health-related quality of life and the effects of steroid use, age, and physical functioning on self-reported health-related quality of life in boys with Duchenne muscular dystrophy. The Pediatric Quality of Life Inventory™ and brief functional measures were administered to 35 parent-son dyads. We found that agreement between parents and their sons was moderate (intraclass correlation coefficient [ICC](2,1) = 0.66; 95% confidence interval [CI], 0.40-0.80) to poor (ICC(2,1) = 0.64; 95% CI, 0.43-0.64). The boys' self-reports revealed a relationship between disease progression and physical functioning (r = -.75; P = .01); however, disease stage was not related to psychosocial functioning (r = -.27; NS). Parents and boys affected by Duchenne muscular dystrophy have a moderate to poor agreement on health-related quality of life measures, with parents reporting lower overall health-related quality of life when compared with their sons.

Asthma-specific Predictors of Smoking Onset in Adolescents with Asthma: A Longitudinal Study

Despite even occasional smoking being more risky for adolescents with asthma, the smoking rate in this vulnerable population remains high. This is the first longitudinal study investigating asthma-specific predictors of smoking initiation. A three-wave longitudinal survey study (22 months) among 257 adolescents with asthma was conducted. The effects of asthma-specific factors [symptom severity, medication adherence, coping, attitude towards asthma, and quality of life (QOL)] on smoking onset were tested with logistic regression models. Poorer self-reported adherence and the maladaptive coping strategy of hiding asthma predicted smoking onset. Poorer QOL predicted smoking in boys only. Our findings underscore the importance of recognizing and addressing adherence problems during adolescence as low adherence is a risk factor for smoking initiation. Moreover, psychosocial factors, such as coping and QOL for boys, were associated with smoking initiation. This highlights the importance of attending to the psychosocial needs of youth with asthma.

Persistent and improved functional gain in mdx dystrophic mice after treatment with L‐arginine and deflazacort

Although an increase in nitric oxide (NO) in muscle is reported to improve the outcome of deflazacort treatment for mdx mouse muscular dystrophy, the genetic homologue of Duchenne muscular dystrophy (DMD), the impact such treatment on the functional outcomes of the disease, including fiber susceptibility to exercise-induced injury, is not established. Experiments were designed to test whether treatment with deflazacort and L-arginine (a substrate for NO synthase, NOS) would change the extent of fiber injury induced by 24 h of voluntary exercise. The impact of exercise-related injury to induce a secondary regenerative response by muscle was also examined as corroborating evidence of muscle damage. Dystrophic mdx mice were treated for 3 wk with placebo, deflazacort, or deflazacort plus either L-arginine or N(G)-nitro-L-arginine methyl ester (a NOS inhibitor). Deflazacort, especially combined with L-arginine, spared quadriceps muscle from injury-induced regeneration (myf5 expression) compared with placebo treatment, despite an increase in membrane permeability immediately after exercise (assessed by Evans blue dye infiltration). Deflazacort alone prevented the typical progressive loss of function (measured as voluntary distance run over 24 h) that was observed 3 months later in placebo-treated mice. Therefore, combined deflazacort plus L-arginine treatment spared mdx dystrophic limb muscle from exercise-induced damage and the need for regeneration and induced a persistent functional improvement in distance run. Results suggest a potential new treatment option for improving the quality of life for boys with DMD.