Comparing family-based treatment with inpatient treatment in youth with anorexia nervosa eligible for hospitalization: A 12-month feasibility study.

OBJECTIVE: Family-based treatment (FBT) for youth with anorexia nervosa (AN), has not been compared to inpatient, multimodal treatment (IMT). METHOD: Prospective, non-randomized pilot feasibility study of adolescents with AN receiving FBT (n = 31), and as a reference point for exploratory outcome comparisons IMT (n = 31), matched for baseline age and percent median BMI (%mBMI). Feasibility of FBT in youth fulfilling criteria for IMT was assessed via study recruitment and retention rates; acceptability via drop-out and caregiver strain; safety via adverse events; preliminary treatment effectiveness between groups was assessed via a change in %mBMI, AN psychopathology (Eating Disorder Examination-Questionnaire, EDE-Q), and hospital days, over 12 months with intent-to-treat, mixed models repeated measures analyses covering post-intervention usual care until 12 months. RESULTS: Taking into account that 8 FBT patients (25.8%) crossed over to IMT due to lack of weight gain or psychiatric concerns, FBT and IMT were similarly feasible, acceptable, and safe, apart from more physical antagonism toward others in FBT (p = .010). FBT lasted longer (median [interquartile range, IQR]; 33.6 [17.4, 49.9] vs. 17.3 [14.4, 24] weeks, p < .001), but required fewer hospital days than IMT (median, [IQR], FBT = 1 [0, 16] vs. IMT = 123 [101, 180], p < .001). Baseline comorbidity-adjusted changes over 12 months did not differ between groups in %mBMI (FBT = 12.6 ± 11.9 vs. IMT = 13.7 ± 9.1; p = .702) and EDE-Q global score (median, [IQR]; FBT = -1.2 [-2.3, 0.2] vs. IMT = -1.3 [-2.8, -0.4]; p = .733). DISCUSSION: Implementing FBT in this pilot study was feasible, acceptable, and safe for youth eligible for IMT according to German S3 guidelines. Non-inferiority of FBT versus IMT requires confirmation in a sufficiently large multicenter RCT. PUBLIC SIGNIFICANCE: This pilot study with 62 adolescent patients with anorexia nervosa demonstrated that for 2/3rd of patients eligible for a long hospitalization in the German health care system, outpatient, Family-based treatment (FBT) was a safe and feasible treatment alternative. Over 12 months, FBT lead to similar weight gain and reduction in eating disorder cognitions as inpatient treatment with fewer hospital days. This pilot study needs to be followed up by a larger, multicenter trial.

Diagnosis of DSD in Children-Development of New Tools for a Structured Diagnostic and Information Management Program within the Empower-DSD Study.

BACKGROUND: Current recommendations define a structured diagnostic process, transparent information, and psychosocial support by a specialized, multi-professional team as central in the care for children and adolescents with genital variations and a suspected difference of sex development (DSD). The active involvement of the child and their parents in shared decision-making should result in an individualized care plan. So far, this process has not been standardized. METHODS: Within the Empower-DSD study, a team of professionals and representatives of patient advocacy groups developed a new diagnostic and information management program based on current recommendations and existing patient information. RESULTS: The information management defines and standardizes generic care elements for the first weeks after a suspected DSD diagnosis. Three different tools were developed: a guideline for the specialized multiprofessional team, a personal health record and information kit for the child with DSD and their family, and a booklet for medical staff not specialized in DSD. CONCLUSIONS: The new information management offers guidance for patients and professionals during the first weeks after a DSD diagnosis is suspected. The developed tools' evaluation will provide further insight into the diagnostic and information-sharing process as well as into all of the involved stakeholders' needs.

Development and evaluation of a patient education programme for children, adolescents, and young adults with differences of sex development (DSD) and their parents: study protocol of Empower-DSD.

BACKGROUND: Differences in sexual development (DSD) are rare diseases, which affect the chromosomal, anatomical or gonadal sex differentiation. Although patient education is recommended as essential in a holistic care approach, standardised programmes are still lacking. The present protocol describes the aims, study design and methods of the Empower-DSD project, which developed an age-adapted multidisciplinary education programme to improve the diagnosis-specific knowledge, skills and empowerment of patients and their parents. METHODS: The new patient education programme was developed for children, adolescents and young adults with congenital adrenal hyperplasia, Turner syndrome, Klinefelter syndrome or XX-/or XY-DSD and their parents. The quantitative and qualitative evaluation methods include standardised questionnaires, semi-structured interviews, and participatory observation. The main outcomes (assessed three and six months after the end of the programme) are health-related quality of life, disease burden, coping, and diagnosis-specific knowledge. The qualitative evaluation examines individual expectations and perceptions of the programme. The results of the quantitative and qualitative evaluation will be triangulated. DISCUSSION: The study Empower-DSD was designed to reduce knowledge gaps regarding the feasibility, acceptance and effects of standardised patient education programmes for children and youth with DSD and their parents. A modular structured patient education programme with four generic and three diagnosis-specific modules based on the ModuS concept previously established for other chronic diseases was developed. The topics, learning objectives and recommended teaching methods are summarised in the structured curricula, one for each diagnosis and age group. At five study centres, 56 trainers were qualified for the implementation of the training programmes. A total of 336 subjects have been already enrolled in the study. The recruitment will go on until August 2022, the last follow-up survey is scheduled for February 2023. The results will help improve multidisciplinary and integrated care for children and youth with DSD and their families. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00023096 . Registered 8 October 2020 - Retrospectively registered.

Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver.

Leukocyte adhesion and transmigration are central features governing immune surveillance and inflammatory reactions in body tissues. Within the liver sinusoids, chemokines initiate the first crucial step of T-cell migration into the hepatic tissue. We studied molecular mechanisms involved in endothelial chemokine supply during hepatic immune surveillance and liver inflammation and their impact on the recruitment of CD4(+) T cells into the liver. In the murine model of Concanavalin A-induced T cell-mediated hepatitis, we showed that hepatic expression of the inflammatory CXC chemokine ligands (CXCL)9 and CXCL10 strongly increased whereas homeostatic CXCL12 significantly decreased. Consistently, CD4(+) T cells expressing the CXC chemokine receptor (CXCR)3 accumulated within the inflamed liver tissue. In histology, CXCL9 was associated with liver sinusoidal endothelial cells (LSEC) which represent the first contact site for T-cell immigration into the liver. LSEC actively transferred basolaterally internalized CXCL12, CXCL9 and CXCL10 via clathrin-coated vesicles to CD4(+) T cells leading to enhanced transmigration of CXCR4(+) total CD4(+) T cells and CXCR3(+) effector/memory CD4(+) T cells, respectively in vitro. LSEC-expressed CXCR4 mediated CXCL12 transport and blockage of endothelial CXCR4 inhibited CXCL12-dependent CD4(+) T-cell transmigration. In contrast, CXCR3 was not involved in the endothelial transport of its ligands CXCL9 and CXCL10. The clathrin-specific inhibitor chlorpromazine blocked endothelial chemokine internalization and CD4(+) T-cell transmigration in vitro as well as migration of CD4(+) T cells into the inflamed liver in vivo. Moreover, hepatic accumulation of CXCR3(+) CD4(+) T cells during T cell-mediated hepatitis was strongly reduced after administration of chlorpromazine. These data demonstrate that LSEC actively provide perivascularly expressed homeostatic and inflammatory chemokines by CXCR4- and clathrin-dependent intracellular transport mechanisms thereby contributing to the hepatic recruitment of CD4(+) T-cell populations during immune surveillance and liver inflammation.

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines.

UNLABELLED: Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4(+) T cells, indicating a mechanism of hepatic immunoregulation. Finally, the results shed light on the molecular mechanisms by which LSEC modulate chemokine-dependent transmigration. LSEC significantly enhanced the chemotactic effect of CXC-motif chemokine ligand 12 (CXCL12) and CXCL9, but not of CXCL16 or CCL20, on naive and memory CD4(+) T cells of a T helper 1, T helper 2, or interleukin-10-producing phenotype. In contrast, brain and lymphatic endothelioma cells and ex vivo isolated lung endothelia inhibited chemokine-driven transmigration. As for the molecular mechanisms, chemokine-induced activation of LSEC was excluded by blockage of G(i)-protein-coupled signaling and the use of knockout mice. After preincubation of CXCL12 to the basal side, LSEC took up CXCL12 and enhanced transmigration as efficiently as in the presence of the soluble chemokine. Blockage of transcytosis in LSEC significantly inhibited this effect, and this suggested that chemokines taken up from the basolateral side and presented on the luminal side of endothelial cells trigger T cell transmigration. CONCLUSION: Our findings demonstrate a unique capacity of LSEC to present chemokines to circulating lymphocytes and highlight the importance of endothelial cells for the in vivo effects of chemokines. Chemokine presentation by LSEC could provide a future therapeutic target for inhibiting lymphocyte immigration and suppressing hepatic inflammation.