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Biomedical subjects

Barbara White

Publications and source records attributed to Barbara White.

At least 19 recordsLinked to original sources
PubMed2006

Cyclophosphamide versus placebo in scleroderma lung disease.

BACKGROUND: We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease. METHODS: At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC. RESULTS: Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant. CONCLUSIONS: One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.

Administration, Oral↗
PubMed2006

Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis.

OBJECTIVE: Previous studies showed that etanercept treatment in patients with polyarticular-course juvenile rheumatoid arthritis (JRA) provided rapid clinical improvement that was sustained for up to 2 years. The goal of our study was to provide data on safety and efficacy after 4 years of etanercept treatment in patients with JRA. METHODS: Patients with active polyarticular-course JRA who participated in an efficacy study continued etanercept treatment in an open-label extension. Safety was assessed by measuring rates of serious adverse events (SAEs) and serious infections. Efficacy was assessed using the American College of Rheumatology (ACR) Pediatric 30 criteria for improvement and standard measures of disease activity. (The ACR Pediatric 30 criteria are defined as improvement of > or = 30% in at least 3 of 6 core response variables used to assess disease activity, with no more than 1 variable worsening by > or = 30%.) RESULTS: Of the 69 patients who enrolled in the original efficacy study, 58 patients (84%) enrolled in the extension, 34 patients received etanercept treatment for > or = 4 years, and 32 of these received complete efficacy assessments. The rate of SAEs was 0.13 per patient-year, and the rate of serious infections was 0.04 per patient-year, in a total etanercept exposure of 225 patient-years. Eighty-two percent of patients who received corticosteroids at any time during the extension were able to decrease their dosage to < or = 5 mg/day prednisone equivalent. Of the 32 patients with complete efficacy data who received etanercept for > or = 4 years, 94% achieved an ACR Pediatric 30 response and 78% achieved an ACR Pediatric 70 response at the last study visit. CONCLUSION: Etanercept offers an acceptable safety profile in children with polyarticular-course JRA and provides significant improvement in disease manifestations that are sustained for > or = 4 years.

Adolescent↗
PubMed2006

Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension.

OBJECTIVE: Lung transplantation is a viable, life-saving intervention for several primary pulmonary disorders complicated by severe lung dysfunction. This study was undertaken to evaluate whether patients with systemic sclerosis (scleroderma), a systemic autoimmune rheumatic disorder, would receive similar benefit from this intervention. METHODS: Survival following lung transplantation was examined at 2 university medical centers among 29 patients with scleroderma as compared with 70 patients with idiopathic pulmonary fibrosis (IPF) and 38 with idiopathic pulmonary arterial hypertension (IPAH), the latter groups representing pathologically related primary pulmonary disorders. The end point was death from any cause. Risk of mortality in patients with scleroderma was compared with that in patients with IPF or IPAH, with adjustment for demographic and clinical parameters. RESULTS: During 2 years of followup, 11 patients with scleroderma (38%), 23 with IPF (33%), and 14 with IPAH (37%) died. Cumulative survival at 6 months posttransplantation was 69% in the scleroderma group compared with 80% in the IPF group (log-rank P = 0.21) and 79% in the IPAH group (P = 0.38). The estimated risk of mortality at 6 months was increased in patients with scleroderma compared with those with IPF (relative risk [RR] 1.70, 95% confidence interval [95% CI] 0.74-3.93) and those with IPAH (RR 1.52, 95% CI 0.59-3.96), but the differences were not statistically significant. Over the following 18 months, there was convergence in the survival rates such that cumulative survival at 2 years was comparable, at approximately 64%, among all 3 groups. CONCLUSION: Patients with scleroderma who are recipients of lung transplantation experience similar rates of survival 2 years after the procedure compared with those with IPF or IPAH. Lung transplantation may represent a viable therapeutic option to consider for patients with end-stage lung disease due to scleroderma.

Adult↗
PubMed2006

Long-term experience with etanercept in the treatment of rheumatoid arthritis in elderly and younger patients: patient-reported outcomes from multiple controlled and open-label extension studies.

BACKGROUND: The impact of long-term therapy for rheumatoid arthritis (RA) in elderly (> or = 65 years of age) and younger (< 65 years of age) patients, especially on patient-reported outcomes, has not been well studied. We evaluated patient-reported outcomes in elderly patients treated with etanercept, in contrast to outcomes in younger patients, using data from multiple controlled and open-label extension studies of patients with early RA (ERA; < or = 3 years) and late RA (LRA; disease-modifying antirheumatic drug [DMARD]-refractory RA). METHODS: This post hoc analysis included adult patients with RA enrolled in controlled, double-blind studies (up to 2 years) and subsequent open-label extension studies (up to 4 years). Patients were evaluated according to age at baseline of the original study. Patients may have received etanercept, placebo or methotrexate during the blinded treatment phases, but all patients had been receiving etanercept 25 mg twice weekly for at least 4 years. Both ERA and LRA extension studies are ongoing. Patient-reported outcome assessments included improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI), proportions of patients achieving an improvement in HAQ-DI > or = 0.22 points, patients exhibiting worsening of HAQ-DI and patients achieving an HAQ-DI score of 0. RESULTS: Elderly patients, with either ERA or LRA, had significantly worse baseline mean HAQ-DI scores than younger patients (p < 0.05, Student's t-test) in most studies, indicating greater disability. Improvement in HAQ-DI was greatest during the first 3 months after starting etanercept treatment in the controlled phase and appeared to be sustained over 3-6 months in patients with early or DMARD-refractory RA. Across the various controlled trials, mean improvements from baseline in HAQ-DI ranged from 0.39 to 0.92 points in elderly patients and from 0.57 to 1.00 points in younger patients. Patients with ERA and LRA, regardless of age group, maintained their improvement in HAQ-DI throughout the open-label extension trials for up to a total of 6 years of etanercept therapy. Change from baseline in HAQ-DI was moderately correlated with 28-joint Disease Activity Score within each age group across the multiple trials. CONCLUSION: Both elderly and younger patients with RA treated with etanercept exhibited similar and rapid improvements in functional status during controlled studies, and these improvements were sustained during open-label extension trials.

Age Factors↗
PubMed2006

Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response.

OBJECTIVE: To determine whether the need to use doses of infliximab greater than 3 mg/kg every 8 weeks to achieve or maintain clinical response in patients with rheumatoid arthritis (RA) is associated with differences in baseline clinical characteristics or anti-infliximab antibodies. METHODS: Baseline clinical characteristics and anti-infliximab levels were evaluated retrospectively in a cohort of 51 consecutive patients with RA treated with infliximab at a single center. Patients were divided into 2 groups for comparison: Group 1 patients achieved and maintained clinical responses with infliximab 3 mg/kg every 8 weeks; Group 2 patients required higher doses. RESULTS: Thirty-two (63%) patients required infliximab dose escalation (Group 2). There were no statistically significant differences in baseline or clinical characteristics between Group 1 and Group 2 patients. Anti-infliximab antibodies occurred in 47% of Group 2 versus 27% of Group 1 patients, with higher anti-infliximab antibody concentrations in Group 2 patients (mean +/- SD: 18.3 +/- 8.9 g/ml vs 7.5 +/- 4.8 g/ml; p = 0.02). Patients who developed anti-infliximab antibodies were younger and receiving less prednisone at the time of infliximab initiation than patients who did not. CONCLUSION: Finding higher anti-infliximab antibody concentrations in patients who needed dose escalation of infliximab to achieve or maintain clinical responses with lower serum trough levels of infliximab suggests that development of anti-infliximab antibodies may reduce clinical efficacy of infliximab in some patients with RA.

Antibodies↗
PubMed2006

Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis.

OBJECTIVE: To evaluate safety and efficacy of etanercept treatment in elderly (age > or = 65 yrs) and younger adult subjects (age < 65 yrs) with rheumatoid arthritis (RA). METHODS: Subset analyses were used to describe the safety and efficacy of etanercept in elderly and younger subjects treated for early and disease modifying antirheumatic drug-resistant or late-stage RA (ERA and LRA) in one of 4 randomized controlled clinical studies (N = 1353) or 2 longterm extensions (N = 1049). RESULTS: Rates of serious adverse events tended to be higher in elderly than younger subjects; however, rates of safety events observed in elderly etanercept-treated subjects did not exceed rates in elderly placebo or methotrexate (MTX)-treated subjects. With regard to efficacy measures [American College of Rheumatology 20% response (ACR20), ACR50, and ACR70], elderly subjects tended to have somewhat less robust responses to treatment than younger subjects. However, for both age groups, treatment with etanercept resulted in improved efficacy and function compared with control treatment, and combination therapy with etanercept plus MTX resulted in greater efficacy than either etanercept or MTX used alone. Efficacy responses of elderly subjects were sustained for up to 6 years. Radiographic progression (measured using modified Sharp Score) after one year of treatment was lower in subjects treated with both etanercept and MTX compared with subjects treated with either agent used alone, and this pattern was similar in both age groups. CONCLUSION: Consistent with responses in younger subjects, elderly subjects with RA treated with etanercept experienced significant improvement in disease activity and function without incurring additional safety concerns.

Age Factors↗
PubMed2006

Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma.

OBJECTIVE: To determine risk factors for developing pulmonary hypertension (PH) in patients with scleroderma (SSc, systemic sclerosis). METHODS: We used a cohort of 1136 SSc patients using severe PH as the primary outcome in a natural history study. RESULTS: Among 361 individuals with no initial echocardiographic PH, 92 (26.0%) developed mild-moderate PH and 48 (13.6%) severe PH. Patients developing severe PH had lower initial DLCO (48.8% of predicted) than those who did not develop PH (56.8% of predicted). Patients with mild-moderate PH had a 17% probability of progressing to severe PH, and 15.6% probability of regressing to no PH. Individuals with limited disease, mild-moderate PH, and age > or= 47 years at diagnosis had a 27.3% probability of developing severe PH, compared to 8.5% in individuals with diffuse disease, no evidence of PH, and age < 47 years at diagnosis. Longitudinal regression models estimated that individuals with limited disease, mild-moderate PH, and DLCO < 50% predicted had an age-adjusted odds ratio of 8.6 of developing severe PH within 2 years compared to individuals without these risk factors. CONCLUSION: Development of severe PH is uncommon in certain subgroups of SSc patients. Risk factors for progression of PH include older age, limited skin disease, and elevated pulmonary artery pressures at the time of initial evaluation.

Adult↗
PubMed2004

Efficacy and tolerability of a selective alpha(2C)-adrenergic receptor blocker in recovery from cold-induced vasospasm in scleroderma patients: a single-center, double-blind, placebo-controlled, randomized crossover study.

OBJECTIVE: OPC-28326 is a selective alpha-adrenergic antagonist with preferential binding to the alpha(2C)-adrenergic receptor (alpha(2C)-AR) subtype. This study observed the effect of OPC-28326 on skin temperature and digital blood flow following an acute cold challenge in patients with Raynaud's phenomenon secondary to scleroderma. METHODS: The study was designed as a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of OPC-28326 (oral doses of 10 mg or 40 mg) or placebo. The primary outcome measures were the time to recover 50% and 70% of the fall (induced by cold challenge) in baseline digital skin temperature. RESULTS: Twelve of 13 enrolled patients completed the study. The mean time to achieve 50% and 70% recovery of the change in prechallenge digital skin temperature was shorter after the OPC-28326 40-mg dose than after placebo (50% recovery at 5.8 minutes versus 10.0 minutes [P = 0.02]; 70% recovery at 13.8 minutes versus 19.5 minutes [P = 0.01]). These recovery times tended to be shorter in the 10 mg OPC-28326 group as well, but the difference versus placebo was not significant (50% recovery at 9.0 minutes versus 10.0 minutes [P = 0.65]; 70% recovery at 15.3 minutes versus 19.5 minutes [P = 0.07]). Total digital blood flow tended to be lower prior to the cold challenge and after administration of 40 mg OPC-28326, as compared with that after placebo, but the difference was not significant. Symptoms that were potentially drug-related were reported more frequently with 40 mg OPC-28326 than with 10 mg OPC-28326 or with placebo, but none were serious or sustained. CONCLUSION: OPC-28326 at doses of 10 mg and 40 mg was well tolerated during this study. The shorter time to skin temperature recovery after 40 mg OPC-28326 suggests that selective alpha(2C)-AR blockade improves digital skin perfusion during recovery from cooling in patients with Raynaud's phenomenon secondary to scleroderma.

Administration, Oral↗
PubMed2004

High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned.

OBJECTIVES: To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine. METHODS: One hundred thirty-four patients with early (< or =18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] D-penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for D-penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses. RESULTS: This RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response. CONCLUSIONS: Even in studies that are therapeutically "negative," careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.

Adult↗
PubMed2004

Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: case study and review of the literature.

Donor-acquired solid organ malignancy is a rare complication of organ transplantation. We report a case of a patient who received bilateral lung transplants for pulmonary fibrosis from a donor with known glioblastoma multiforme (GBM). The lungs, heart, liver, and kidneys were harvested after a lethal intracranial bleed and accepted for transplantation by four centers. An enlarged hilar lymph node sampled at the time of transplant was found to contain GBM. Four months later, the patient developed diffuse interstitial pulmonary infiltrates with mediastinal lymphadenopathy. Lung biopsy confirmed metastatic GBM. The patient died 2 weeks after the diagnosis was established. The patient receiving the donor liver also developed GBM. We present a case study, review of the literature, and suggested interventions to minimize the risk of transmission.

Adult↗
PubMed2003

Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblasts.

Levels of pulmonary and activation-regulated chemokine (PARC) mRNA and protein are increased in the lungs of patients with pulmonary fibrosis. The purpose of this study was to establish whether PARC could be directly involved in development of pulmonary fibrosis by stimulating collagen production in lung fibroblasts. Exposure to PARC increased production of collagen mRNA and protein by 3- to 4-fold in normal adult lung and dermal fibroblast cells. Collagen mRNA transiently increased after 3-6 h of activation with PARC, with an increase in collagen protein detected after 24 h of activation. At the same time, PARC had less pronounced effect on fibroblast proliferation, not exceeding 50% increase over control nonstimulated cells. PARC intracellular signaling led to activation of ERK1/2, but not p38, in fibroblasts; pharmacologic inhibition of ERK, but not p38, also blocked PARC's effect on collagen production. Inhibition experiments with pertussis toxin suggested that PARC receptor is G protein-coupled. Thus, PARC is a member of the CC chemokine family that acts directly as a profibrotic factor.

Cells, Cultured↗
PubMed2003

Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients.

OBJECTIVE: Pulmonary fibrosis is a major cause of death in scleroderma patients. Previous studies have shown an increase in CD8+ T cells in the lungs of scleroderma patients. In the present study, we sought to determine whether activated CD8+ T cells contribute to pulmonary fibrosis in scleroderma patients through the production and activation of profibrotic mediators. METHODS: CD8+ cells were isolated from bronchoalveolar lavage fluid obtained from 19 scleroderma patients and 7 healthy subjects. The phenotype of these cells was determined using DNA array technology. Expression of selected genes was confirmed in real-time polymerase chain reaction and enzyme-linked immunosorbent assay experiments. RESULTS: Hierarchical clustering of gene expression profiles revealed 2 groups of subjects. Group 1 consisted of 11 patients (8 with and 3 without lung inflammation). Group 2 consisted of 15 subjects (7 healthy controls and 2 patients with and 6 without lung inflammation). Gene expression in group 1 indicated T cell activation, a type 2 phenotype, production of profibrotic factors and matrix metalloproteinases, and reduced activation-induced cell death. Increased expression of beta6 integrin messenger RNA by CD8+ T cells in group 1 suggested the possibility that these T cells might induce cell-contact-dependent activation of latent transforming growth factor beta (TGFbeta). CONCLUSION: A subset of scleroderma patients at higher risk of progressive lung disease have activated, long-lived CD8+ T cells in their lungs that could promote fibrosis directly, through production of profibrotic factors such as interleukin-4 and oncostatin M, as well as indirectly, through activation of TGFbeta.

Adult↗
PubMed2003

Interstitial lung disease in scleroderma.

Pulmonary fibrosis occurs most patients who have scleroderma. It progresses to severe restrictive lung disease in about 15% of patients and remains a major cause of death in this disease. Risks for developing pulmonary fibrosis include diffuse cutaneous scleroderma and anti-Scl-70 antibodies, and risks for developing progressive pulmonary fibrosis and death include low pulmonary function test results at presentation and lung inflammation. Early evaluation of the extent and severity of pulmonary fibrosis and the presence of lung inflammation is key, so that therapy can be given to patients who are at higher risk of progressive pulmonary fibrosis before they develop severe functional impairment occurs. Evaluation often includes pulmonary function tests, HRCT of the lungs, Doppler echocardiogram, and bronchoalveolar lavage. For patients who are unwilling or unable to participate in therapeutic trials that target pulmonary fibrosis in scleroderma, therapy with oral or intravenous cyclophosphamide is often given.

Humans↗
PubMed2003

Cytokine regulation of pulmonary fibrosis in scleroderma.

Pulmonary fibrosis occurs in up to 70% of scleroderma patients and progresses to cause severe restrictive lung disease in about 15% of patients. The mechanisms that cause pulmonary fibrosis in scleroderma remain incompletely understood. Increased amounts of mRNA or protein for multiple profibrotic cytokines and chemokines have been identified in lung tissue or broncholveolar lavage samples from scleroderma patients, when compared to healthy controls. These cytokines include transforming growth factor (TGF)-beta, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), oncostatin M (OSM), monocyte chemotactic factor-1 and pulmonary and activation-regulated chemokine (PARC). Potential cellular sources of these profibrotic cytokines and chemokines in scleroderma lung disease include alternatively activated macrophages, activated CD8+ T cells, eosinophils, mast cells, epithelial cells and fibroblasts themselves. This review summarizes the literature on involvement of cytokines and chemokines in the development of pulmonary fibrosis in scleroderma.

Adult↗
PubMed2003

The role of chemokines in the pathogenesis of scleroderma.

PURPOSE OF REVIEW: The triad of pathologic changes that defines systemic sclerosis (scleroderma) includes immune system activation with autoimmunity; an obliterative, proliferative small vessel vasculopathy; and fibrosis. Available data suggest that several cytokines, including chemokines, contribute to the development of scleroderma complications. This review focuses on chemokines and their contribution to tissue fibrosis and pulmonary hypertension in scleroderma. RECENT FINDINGS: Proteins and mRNAs for monocyte chemoattractant protein-1; pulmonary and activation-regulated chemokine; macrophage inflammatory protein-1, regulated upon activation normal T cell expressed and secreted; interleukin-8; and transforming growth factor-beta have been found in increased amounts in blood or involved tissue from scleroderma patients. These factors are likely to contribute directly to tissue damage in scleroderma through several pathways, including stimulation of extracellular matrix production, induction of TGF-beta production and activation, and chemoattraction of T cells and nonspecific inflammatory cells into tissues. SUMMARY: Multiple chemokines are part of the pathologic network that causes tissue damage in scleroderma, and, as such, may provide therapeutic targets in scleroderma.

Animals↗
PubMed2003

Age and risk of pulmonary arterial hypertension in scleroderma.

STUDY OBJECTIVES: To investigate whether age at disease onset is a risk factor for pulmonary arterial hypertension (PAH) in scleroderma. SETTING: Scleroderma center. PATIENTS: Seven hundred nine consecutive scleroderma patients who underwent echocardiography. MEASUREMENTS: The risk of PAH associated with age at disease onset was modeled as both a continuous and categorical variable. Risk estimates were adjusted for sex, race, scleroderma subtype, disease duration, smoking status, FVC, anticentromere and antitopoisomerase I antibody status. RESULTS: Overall, 274 patients (38.6%), 272 patients by Doppler echocardiography and 2 patients by M-mode echocardiography, had PAH at baseline or during follow-up. There were 114 patients with mild PAH (right ventricular systolic pressure [RVSP], 36 to 45 mm Hg), 66 patients with moderate PAH (RVSP, 46 to 55 mm Hg), and 92 patients with severe PAH (RVSP > or =56 mm Hg). A 52% increase in risk of PAH was demonstrated for every 10 years of age at disease onset (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.31 to 1.76). In addition, there was a twofold greater risk of PAH (OR, 2.30; 95% CI, 1.32 to 3.99) for late-onset (age > or =60 years) vs earlier-onset (< 60 years) disease. These associations remained evident and were somewhat strengthened when the analyses were restricted to patients with moderate and severe PAH. CONCLUSIONS: We identified increasing age at scleroderma onset as a risk factor for PAH. Vigilance among these high-risk patients may provide an opportunity to intervene prior to development of irreversible pulmonary vascular disease.

Adolescent↗
PubMed2003

Body image dissatisfaction among women with scleroderma: extent and relationship to psychosocial function.

Body image dissatisfaction and its relationship to psychosocial function were investigated in 127 women with scleroderma Results indicated elevated body image dissatisfaction, with participants reporting higher levels than a sample of patients with severe burn injuries. Age, skin tightening above the elbows, and functional disability were related to heightened body image dissatisfaction, suggesting that younger patients with more severe disease may be at greatest risk for developing body image concerns. Path analysis revealed that depression mediated the relationship between body image dissatisfaction and psychosocial function. Results suggest that body image dissatisfaction is a significant concern in women with scleroderma and should be assessed routinely. Early identification and treatment of body image dissatisfaction may help prevent the development of depression and psychosocial impairment in this population.

Adaptation, Psychological↗