UK guideline on the transition and management of childhood liver diseases in adulthood.

INTRODUCTION: Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. AIMS: To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. METHODS: A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. CONCLUSIONS: These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.

Self-management skills in a UK sample of young people with chronic liver disease.

BACKGROUND: We aimed to assess self-management skills and adherence behaviors in young people post-liver transplant and compare these with those of young people with autoimmune liver disease and other forms of chronic liver disease. METHOD: As part of our specialist multidisciplinary clinic, n = 156 young people (aged 16-25 years) completed the Liver Self-Management Questionnaire (an adaptation of the Developmentally Based Skills Checklist for adolescents post-liver transplant and modified for us across liver disease type and within the United Kingdom). Those taking medication (n = 128) also completed a service-designed questionnaire regarding adherence. The statistical significance of group differences was assessed with non-parametric analyses. RESULTS: Young people post-liver transplant were less likely to report managing their condition independently than those with autoimmune liver disease or those with other forms of chronic liver disease. They also reported higher adherence (93%) compared to those with autoimmune liver disease (77%) and those with other forms of chronic liver disease (85%). However, the vast majority of self-management and adherence behaviors were comparable between young people post-transplant and those with autoimmune liver disease/other forms of chronic liver disease. CONCLUSION: Our data are in line with existing data from US samples and also extend these findings to include those with other forms of chronic liver disease. These data highlight the importance of individualized care for young adults, regardless of condition type or healthcare setting, and of clinicians managing their expectations regarding what is considered appropriate condition management in early adulthood.

Outcomes of adults who received liver transplant as young children.

BACKGROUND: Patient and graft survival 20-years after pediatric liver transplantation (pLT) are excellent. In children, attainment of normal growth, education and social adaptation to be an independent adult are equally important. This is particularly relevant for children who receive liver transplant at a young age, where infantile-onset liver disease, surgery and immunosuppression can adversely affect growth and neurodevelopment. The aim of this study was to evaluate the long-term physical and psychosocial outcomes of pLT recipients with normal graft function. We coin the term 'meaningful survival'. METHODS: We performed a cross-sectional study of pLT recipients who received transplants between 1985 and 2004. A 20-year evaluation of physical health (growth, renal function), mental wellbeing and social outcomes (substance abuse, adherence, education, employment) was performed. All patients included were considered to have normal graft function. FINDINGS: Eighty-four patients met study criteria. Median age at transplantation was 1.3 years (IQR 0·7-3·3 years), with median duration of follow-up of 20.2 years (18·0-23·5). At median of 20-years, 19 patients (23%) had chronic renal dysfunction and 3 patients (4%) had a BMI of >30 (mean 20·4). Evaluation of long-term psychosocial outcomes demonstrated 22 patients (26%) with mental health disorders. Substance abuse was lower than national average. 62 patients (74%) were in education, employment or training. Overall, only 26% of our cohort achieved a composite outcome of 'meaningful survival'. INTERPRETATION: This is the largest reported long-term study of biopsychosocial outcomes of pLT recipients with normal liver biochemistry, with follow-up upon completion of physical growth and senior school education. Importantly, despite normal liver function, many patients did not demonstrate 'meaningful survival'. We must refocus our efforts towards better understanding the long-term outcomes of children. A 'meaningful survival' rather than mere survival should be our goal. FUNDING: None.

Adherence, Mental Health and Illness Perceptions in Autoimmune Liver Disease: Looking Beyond Liver Function Tests.

OBJECTIVES: Autoimmune liver disease is commonly diagnosed during adolescence; a period associated with a higher prevalence of non-adherence, mental health concerns and worse health outcomes. The aim of the study was to explore adherence patterns, mental health and illness perceptions in young people with autoimmune liver disease. METHODS: Young people with autoimmune liver disease attending a multidisciplinary young adult clinic (16-25 years) completed an electronically administered questionnaire battery. Demographics and disease-related data were collected. RESULTS: Sixty-eight (37 female), median age 17.9 (range 15-22) years completed the screening. Only 51.5% of patients were in remission (aspartate and alanine aminotransferase <36 IU//l) whereas 73% self-reported their adherence >80%. Compared to patients in remission, those not in remission required more immunosuppression, were more depressed and worried but reported a better understanding of their illness. A small but significant correlation was found between aspartate aminotransferase/alanine aminotransferase and adherence percentage (r = -0.27, P < 0.05 and r = -0.29, P < 0.05 respectively). Age was inversely associated with adherence (r = -0.31, P < 0.05), and older patients were more worried (r = 0.44, P < 0.001) and emotionally affected by the condition (r = 0.32, P < 0.01). Adherence behaviours such as forgetting to take medications (63%), taking medications more frequently before attending appointments (44%) and not having a routine for medications (31%) were prevalent, 7% reported intentional non-adherence. CONCLUSION: Sup-optimal adherence to treatment is common in young people with autoimmune liver disease and associated with mental health problems and certain illness perceptions. Routine exploration of adherence beliefs and barriers to adherence in a non-judgmental, collaborative way is essential to improve outcome in this vulnerable population.

Mental Health, Cognitive, and Neuropsychiatric Needs in Children and Young People With Wilson Disease.

Wilson disease (WD) is associated with neurological, psychiatric, cognitive, and psychosocial difficulties, but there is little data regarding the nature and prevalence of these problems in children and young people (CYP). Methods: A single-center case-note review to establish the incidence and nature of these issues in CYP with WD, managed before and after multidisciplinary team (MDT) clinics, was established. Results: Out of 69 (43 males) CYP with WD, 37.8% presented with acute liver failure, 48.6% with chronic liver disease and 13.5% after family screening. Medical treatment was with penicillamine (40), trientene (18), zinc and penicillamine/trientene (11), and zinc monotherapy (2). Twenty-one underwent liver transplantation. After a median follow-up of 9.8 (IQR 6.4-16.9) years, 86% are alive. Six died posttransplantation and 7 grafts were lost. Mental health difficulties were recorded in 49.3%, particularly prevalent in the acute liver failure group (70.8%). Nonadherence was common (50.7%) and associated with greater mental health prevalence. Neurological issues were reported in 36.2% and poor cognition/attainment in 14.5%, consistent across modes of presentation. Four patients had diagnoses of autism spectrum conditions, all diagnosed pre WD. CYP seen within an MDT-clinic had more frequent documentation of all issues examined, but lower levels of late graft loss (94% versus 80%, P = 0.07). Conclusion: Our data highlight the need to offer management in WD patients especially as these aspects are underrecognized in CYP presenting with liver involvement. We aim to highlight the importance of multidisciplinary input when looking after this population beyond transition through to adult services.

The Plasmodium falciparum Hsp70-x chaperone assists the heat stress response of the malaria parasite.

Plasmodium falciparum is the most lethal of human-infective malaria parasites. A hallmark of P. falciparum malaria is extensive remodeling of host erythrocytes by the parasite, which facilitates the development of virulence properties such as host cell adhesion to the endothelial lining of the microvasculature. Host remodeling is mediated by a large complement of parasite proteins exported to the erythrocyte; among them is a single heat shock protein (Hsp)70-class protein chaperone, P. falciparum Hsp70-x (PfHsp70-x). PfHsp70-x was previously shown to assist the development of virulent cytoadherence characteristics. Here, we show that PfHsp70-x also supports parasite growth under elevated temperature conditions that simulate febrile episodes, especially at the beginning of the parasite life cycle when most of host cell remodeling takes place. Biochemical and biophysical analyses of PfHsp70-x, including crystallographic structures of its catalytic domain and the J-domain of its stimulatory Hsp40 cochaperone, suggest that PfHsp70-x is highly similar to human Hsp70 chaperones endogenous to the erythrocyte. Nevertheless, our results indicate that selective inhibition of PfHsp70-x function using small molecules may be possible and highlight specific sites of its catalytic domain as potentially of high interest. We discuss the likely roles of PfHsp70-x and human chaperones in P. falciparum biology and how specific inhibitors may assist us in disentangling their relative contributions.-Day, J., Passecker, A., Beck, H.-P., Vakonakis, I. The Plasmodium falciparum Hsp70-x chaperone assists the heat stress response of the malaria parasite.

Plasmodium falciparum Plasmodium helical interspersed subtelomeric proteins contribute to cytoadherence and anchor P. falciparum erythrocyte membrane protein 1 to the host cell cytoskeleton.

Adherence of Plasmodium falciparum-infected erythrocytes to host endothelium is conferred through the parasite-derived virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major contributor to malaria severity. PfEMP1 located at knob structures on the erythrocyte surface is anchored to the cytoskeleton, and the Plasmodium helical interspersed subtelomeric (PHIST) gene family plays a role in many host cell modifications including binding the intracellular domain of PfEMP1. Here, we show that conditional reduction of the PHIST protein PFE1605w strongly reduces adhesion of infected erythrocytes to the endothelial receptor CD36. Adhesion to other endothelial receptors was less affected or even unaltered by PFE1605w depletion, suggesting that PHIST proteins might be optimized for subsets of PfEMP1 variants. PFE1605w does not play a role in PfEMP1 transport, but it directly interacts with both the intracellular segment of PfEMP1 and with cytoskeletal components. This is the first report of a PHIST protein interacting with key molecules of the cytoadherence complex and the host cytoskeleton, and this functional role seems to play an essential role in the pathology of P. falciparum.

An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1 -antitrypsin upon ligand binding.

Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)-MS can report on conformational behavior of specific states. We used IM-MS to study a conformationally labile protein (α1 -antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z-variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild-type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z α1 -antitrypsin polymerogenicity. We show the ability of IM-MS to track such disease-relevant conformational behavior in detail by studying the effects of peptide binding on α1 -antitrypsin conformation and dynamics. IM-MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native α1 -antitrypsin. Our findings are confirmed with high-resolution X-ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue-specific level. IM-MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest.

Risk factors, correlates, and markers in early-onset bulimia nervosa and EDNOS.

OBJECTIVE: This study aimed to investigate the specific risk factors, correlates, and markers associated with the development of symptomatology of early-onset BN and subclinical BN. METHOD: Two semi-structured interviews were used to examine symptomatology and antecedent factors of bulimic symptoms in a sample of British adolescents. RESULTS: Adolescents with early-onset eating pathology were significantly more likely to report an earlier age of menarche than those developing the disorder at the typical age, and were found to have a different pathway of symptom development. DISCUSSION: Increased awareness of this may help identify those particularly at risk for developing an early-onset of eating pathology.

Quetiapine treatment and improved cognitive functioning in borderline personality disorder.

OBJECTIVE: We aimed to assess whether executive functioning improved over time in a sample of borderline personality disorder (BPD) subjects that took part in a quetiapine treatment trial. METHODS: Performance on the following neurocognitive tasks was assessed at enrolment and at the end of the 12 weeks quetiapine treatment: Trail Making Task, Word Fluency Task and Tower of London Task. Forty-one BPD patients were recruited, of whom 32 completed the trial. An intention-to-treat analysis with a mixed linear model was applied. RESULTS: The data show that participants significantly improved on most executive functioning measures. Patients' scores decreased significantly (mean [SD] difference; p-value) on the Trail Making Task Part A (11.7 [2.3]; p < 0.0001), Part B (51.8 [9.2]; p < 0.0001) and 'B minus A' (40.1 [8.2]; p < 0.0001), on a Phonological (15.9 [1.6]; p < 0.0001) and Semantic (9.8 [1.1]; p < 0.0001) Verbal Fluency tasks, and on the Tower of London total correct score (2.5 [0.4]; p < 0.0001), total move score (29.5 [4.5]; p < 0.0001) and total time (172.9 [35.8]; p < 0.0001). CONCLUSIONS: In this study we have demonstrated that executive functioning in BPD is improved after treatment with quetiapine. Neurocognitive measures of executive functioning should be considered as valuable outcomes in the study of treatment efficacy in BPD.

Eating disorders and obesity: two sides of the same coin?

The eating disorders anorexia and bulimia nervosa have traditionally been regarded as entirely separate from obesity. Eating disorders have been regarded as Western culture-bound syndromes, arising in societies with excessive emphasis on weight, shape and appearance, and best treated by psychological therapies, in particular cognitive behavioural therapy or family-based interventions. In contrast, obesity has been considered a medical illness with metabolic and genetic origins, and thought to be best treated by mainstream medicine, involving dietary, drug or surgical treatment. We believe that this polarisation is fundamentally flawed, and research and treatment of both types of disorder would be better served by greater appreciation of the psychosocial components of obesity and the biological and genetic components of eating disorders. There are similarities in phenotype (such as excessive attempts at weight control, binge eating behaviours) and in risk factors (such as low self-esteem, external locus of control, childhood abuse and neglect, dieting, media exposure, body image dissatisfaction, weight-related teasing and shared susceptibility genes). One example of shared genetic risk is the brain-derived neurotrophic factor (BNDF) gene, in which the valine allele of the Val66Met amino acid polymorphism predisposes to obesity, whereas the methionine allele predisposes to eating disorders. Thus the evidence suggests that these disorders will have both shared and distinct susceptibility factors; some will predispose to both types of disorder, some will push in opposite directions, and some will separate them.