A longitudinal, observational study of the features of transitional healthcare associated with better outcomes for young people with long-term conditions.

BACKGROUND: Most evidence about what works in transitional care comes from small studies in single clinical specialties. We tested the hypothesis that exposures to nine recommended features of transitional healthcare were associated with better outcomes for young people with long-term conditions during transition from child-centred to adult-oriented health services. METHODS: This is a longitudinal, observational cohort study in UK secondary care including 374 young people, aged 14-18.9 years at recruitment, with type 1 diabetes (n = 150), cerebral palsy (n = 106) or autism spectrum disorder with an associated mental health problem (n = 118). All were pre-transfer and without significant learning disability. We approached all young people attending five paediatric diabetes centres, all young people with autism spectrum disorder attending four mental health centres, and randomly selected young people from two population-based cerebral palsy registers. Participants received four home research visits, 1 year apart and 274 participants (73%) completed follow-up. Outcome measures were Warwick Edinburgh Mental Wellbeing Scale, Mind the Gap Scale (satisfaction with services), Rotterdam Transition Profile (Participation) and Autonomy in Appointments. RESULTS: Exposure to recommended features was 61% for 'coordinated team', 53% for 'age-banded clinic', 48% for 'holistic life-skills training', 42% for 'promotion of health self-efficacy', 40% for 'meeting the adult team before transfer', 34% for 'appropriate parent involvement' and less than 30% for 'written transition plan', 'key worker' and 'transition manager for clinical team'. Three features were strongly associated with improved outcomes. (1) 'Appropriate parent involvement', example association with Wellbeing (b = 4.5, 95% CI 2.0-7.0, p = 0.001); (2) 'Promotion of health self-efficacy', example association with Satisfaction with Services (b = - 0.5, 95% CI - 0.9 to - 0.2, p = 0.006); (3) 'Meeting the adult team before transfer', example associations with Participation (arranging services and aids) (odds ratio 5.2, 95% CI 2.1-12.8, p < 0.001) and with Autonomy in Appointments (average 1.7 points higher, 95% CI 0.8-2.6, p < 0.001). There was slightly less recruitment of participants from areas with greater socioeconomic deprivation, though not with respect to family composition. CONCLUSIONS: Three features of transitional care were associated with improved outcomes. Results are likely to be generalisable because participants had three very different conditions, attending services at many UK sites. Results are relevant for clinicians as well as for commissioners and managers of health services. The challenge of introducing these three features across child and adult healthcare services, and the effects of doing so, should be assessed.

Parents in transition: Experiences of parents of young people with a liver transplant transferring to adult services.

Predictors of successful transition from pediatric to adult services include ability to self-manage and engage with healthcare services. Parents have a key role in healthcare management throughout childhood and adolescence including encouraging development of self-management skills in their children. Transition to adult services can be challenging for parents and young people, yet parents' views regarding transition remain largely unexplored. Nine parents of pediatric liver transplant recipients (15.2-25.1 yr) participated in semistructured interviews. Interviews were analyzed using IPA. Analysis revealed three key themes: "emotional impact of transplantation," "protection vs. independence," and "ending relationships and changing roles." Parents expressed the dichotomous nature of the desire to promote independence in their child while still maintaining control and protection, and discussed how changing roles and relationships were difficult to navigate. Parents are important facilitators of young people's development of self-management skills for successful transfer to adult services. Parents should be supported to move from a "managerial" to a "supervisory" role during transition to help young people engage independently with the healthcare team. Findings support the development of interventions for parents to emphasize their role in transition and guide the transfer of self-management skills from parent to young person.

"Are these adult doctors gonna know me?" Experiences of transition for young people with a liver transplant.

Excellent survival rates in paediatric LTx have resulted in increasing numbers of young people transferring from paediatric to adult care. Understanding the mechanisms of successful transition is imperative for ensuring good long-term outcomes and developing services for young people. Semi-structured interviews were conducted with 17 young people (10 females; age range: 15.2-25.1 years). Eight were within 1 year of transferring to adult services; nine had transferred. Interviews were analysed using IPA. Analysis revealed two major themes in both pre- and post-transfer groups: "relationships with healthcare professionals" and "continuity of care." Young people experienced difficulty ending relationships with paediatric clinicians and forming new relationships with adult clinicians. They expressed frustrations over a perceived lack of continuity of care after transfer and a fear of the unknown nature of adult services. The importance of a holistic approach to care was emphasized. Interventions are needed to support young people in transition, particularly in ending relationships in paediatric care and forming new relationships in adult care. Young people need help to develop strategies to cope with the different approaches in adult services. Interventions to provide clinicians with skills to communicate and engage with young people are imperative.

A review of methods for the calculation of solution free energies and the modelling of systems in solution.

Over the past decade, pharmaceutical companies have seen a decline in the number of drug candidates successfully passing through clinical trials, though billions are still spent on drug development. Poor aqueous solubility leads to low bio-availability, reducing pharmaceutical effectiveness. The human cost of inefficient drug candidate testing is of great medical concern, with fewer drugs making it to the production line, slowing the development of new treatments. In biochemistry and biophysics, water mediated reactions and interactions within active sites and protein pockets are an active area of research, in which methods for modelling solvated systems are continually pushed to their limits. Here, we discuss a multitude of methods aimed towards solvent modelling and solubility prediction, aiming to inform the reader of the options available, and outlining the various advantages and disadvantages of each approach.

Walking the talk. Implementation of transitional care guidance in a UK paediatric and a neighbouring adult facility.

OBJECTIVES: To examine the quality of transitional care in a paediatric and adult hospital by investigating (i) adherence to national transition guidance and (ii) whether implementation is associated with better patient/carer experiences. METHODS: A cross-sectional study was conducted in a UK paediatric hospital (PH) and neighbouring adult hospital. Clinics completed a questionnaire to determine characteristics of their transitional care provision and invited patients aged 11-21 years and parents/carers to complete a questionnaire ('Mind the Gap') to assess their satisfaction. RESULTS: Twenty-three clinics participated. Fourteen (70%) reported delivering a transition programme, but only 5 (25%) indicated this was holistic (addressing medical, psychosocial and vocational issues). Participants included 457 young people and 330 parents, 71% and 88% respectively attending the PH. Ratings of current care were significantly lower than ratings of best care. These 'gap' scores were not excessive, although some participants were very dissatisfied. Better satisfaction was associated with attending clinics that provided transitional care, especially when defined as 'holistic' and youth-friendly. CONCLUSIONS: Transition programmes that adhere to current guidance are associated with better satisfaction, but variations in provision suggest barriers to implementation. Attention is required to how youth-friendly transitional care is defined with particular reference to the specific clinic model.

The challenges and opportunities for transitional care research.

The provision of healthcare for young people with solid organ transplants as they move into adult-centered services has received increasing attention over recent years particularly as non-adherence and graft loss increase after transfer. Despite medical advances and that transitional care is now well established on national and international health agendas, progress in the research arena has unfortunately been slow. The aims of this paper are to consider why this is and discuss the particular challenges facing clinical researchers working within the area.

Fibronectin molecule visualized in electron microscopy: a long, thin, flexible strand.

We have determined the structure of plasma fibronectin by electron microscopy of shadowed specimens. the 440,000 molecular weight, dimeric molecule appears to be a long, thin, highly flexible strand. The contour length of the most extended molecules is 160 nm, but a distribution of lengths down to 120 nm was observed, indicating flexibility in extension as well as in bending. The average diameter of the strand is 2 nm and there are no large globular domains. the large fragments produced by limited digestion with plasmin are not globular domains but are segments of the strand, whose length corresponds to the molecular weight of the polypeptide chain. We conclude that each polypeptide chain of the dimeric molecule spans half the length of the strand, with their carboxyl termini joined at the center of the strand and their amino termini at the ends. This model is supported by images of fibronectin-fibrinogen complexes, in which the fibrinogen is always attached to an end of the fibronectin strand.

Regulation of extravascular coagulation by microvascular permeability.

Extravascular coagulation is a prominent feature of such important pathological processes as cellular immunity and neoplasia and has been thought to result from procoagulants associated with the inflammatory or tumor cells peculiar to these entities. It was found that increased microvascular permeability alone is sufficient to induce equivalent extravascular coagulation in several normal tissues. The results indicate that saturating levels of procoagulant are present even in normal tissues and that microvascular permeability is a rate-limiting step in extravascular coagulation.

Binding and covalent cross-linking of purified von Willebrand factor to native monomeric collagen.

We have analyzed the interaction of the adhesive glycoprotein, von Willebrand factor (vWF), with native monomeric collagen monolayers by adsorbing acid soluble Types I and III collagen derived from calf skin to polystyrene microtiter wells and incubating the wells with purified human 125I-vWF. The binding of 125I-vWF was saturable, reversible, specific, and was abolished by heat denaturation of the collagen monomers. Binding was half-maximal at 5 micrograms/ml, and, at saturation, 7.5 ng 125I-vWF were bound to each microgram of immobilized collagen. 125I-vWF did not bind to wells coated with other extracellular matrix or plasma proteins such as fibronectin, fibrinogen, gelatin, or the q subunit of the first component of complement (C1q). In addition, bound 125I-vWF could not be displaced from collagen by the addition of either fibronectin or fibrinogen. After incubation with Factor XIIIa, plasma transglutaminase, 125I-vWF bound to collagen could no longer be displaced by vWF, which suggests covalent cross-linking of vWF to collagen monomers. Factor XIIIa-dependent covalent cross-linking of vWF to collagen, but not to fibronectin or laminin, was also demonstrated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate.

Identification of intracellular factor XIII in human monocytes and macrophages.

Factor XIII is a blood protransglutaminase that is distributed in plasma and platelets. The extracellular and intracellular zymogenic forms differ in that the plasma zymogen contains A and B subunits, while the platelet zymogen has A subunits only. Both zymogens form the same enzyme. Erythrocytes, in contrast, contain a tissue transglutaminase that is distinct from Factor XIII. In this study other bone marrow-derived cells were examined for transglutaminase activity. Criteria that were used to differentiate Factor XIII proteins from erythrocyte transglutaminase included: (a) immunochemical and immunohistochemical identification with monospecific polyclonal and monoclonal antibodies to Factor XIII proteins, (b) requirement for thrombin cleavage to express activity, (c) pattern of fibrin cross-linking catalyzed by the enzyme, and (d) different electrophoretic mobilities in nondenaturing gel systems. By these criteria human peripheral blood monocytes, peritoneal macrophages, and monocytes maintained in culture contain an intracellular protransglutaminase that is the same as platelet Factor XIII. The monocyte-macrophage protein is thrombin-sensitive, and under appropriate conditions there is no enzyme expression without activation of the zymogen. Both the monocyte-macrophage zymogen and enzyme have the same electrophoretic mobilities as platelet Factor XIII zymogen and enzyme. Antibody to A protein reacts with the monocyte-macrophage protein. B protein is not associated with this intracellular zymogen. By immunoperoxidase staining monocyte-macrophage protein seems to be localized in the cytoplasm, similar to the known cytoplasmic distribution of platelet and megakaryocyte Factor XIII. These procedures were also used to study populations of human granulocytes and lymphocytes, and protransglutaminase activity was not observed in these cells.

Factor XIII in human plasma and platelets.

Plasma and platelet factor XIII levels were measured in normal human donors and in a patient congenitally deficient in factor XIII. The purpose of these experiments was to study the role of platelet factor XIII in blood coagulation. On polyacrylamide disc electrophoresis, factor XIII activity in extracts of washed normal platelets appeared as a single peak. This peak was missing or very low when factor XIII-deficient platelet extract was used. The patient was also studied before and after transfusion of fresh frozen plasma. Before transfusion, factor XIII activity could not be detected in the patient's plasma or platelet extracts. 24 hr after transfusion the plasma factor XIII level was still at the anticipated value, but factor XIII activity could not be detected in the platelet extracts. These experiments imply that plasma factor XIII was not transported across the platelet membrane in measurable quantities in vivo. This suggests that platelet factor XIII is a true platelet component and originates in the platelet precursor, the megakaryocyte. Thrombelastographic studies suggest that platelet factor XIII participates in the coagulation process. Thrombelastograms of factor XIII-deficient samples had decreased maximum amplitude and clot elasticity values. The abnormalities were fully corrected by the addition of washed normal platelets to factor XIII-deficient plasma; preincubation of the normal platelets in the deficient plasma had no additional effect. This indicates that platelet factor XIII is immediately available during clot formation.

Difference between type I autoimmune inhibitors of fibrin stabilization in two patients with severe hemorrhagic disorder.

Inhibitors of fibrin stabilization of apparently autoimmune origin, found in two severely bleeding unrelated patients (W. G. and G. A.), were compared with regard to their biological target specificities, potencies and immunological characteristics. Both interfered only with the activation of fibrin stabilizing factor (coagulation Factor XIII) and, while totally preventing the conversion of this zymogen to the functional transamidating enzyme, fibrinoligase (Factor XIII(a)), they showed very little inhibition toward the enzyme itself. Thus, according to the classification of Lorand concerning biological specificities, both can be characterized as Type I inhibitors of fibrin stabilization. Potencies of the two inhibitors were quite similar when measured in conjunction with the plasma zymogen, but they differed remarkably in tests with platelet Factor 13. The inhibitor of patient W. G. prevented the activation of the zymogen from platelets, but that of G. A. had no effect on the platelet factor. It may therefore be concluded that the inhibitor of W. G. is directed exclusively against the a subunit which is a common constituent of plasma as well as platelet factors. The inhibitor of G. A., however, must be targeted against determinants uniquely characteristic for the ab ensemble of the plasma zymogen including the b subunit. On the basis of this difference in target specificity, the inhibitor of W. G. is designated as Type I-1 and that of G. A. as Type I-2. The inhibitors of both patients were isolated as immunoglobulins, and neutralization tests revealed that the antibody of W. G. comprised mainly heavy chains of the IgG1 and light chains of the kappa class. The antibody of G. A. proved to be considerably more heterogeneous and contained IgG1 and IgG3 heavy chains as well as kappa- and lambda-light chains. The finding that the antibody of W. G. inhibited conversion of platelet Factor 13 and also its thrombinmodified form, but had no effect on the thrombin and Ca(2+)-activated factor, is an indication that antigenic determinants existing both on the native zymogen and on its hydrolytically modified form become buried in the Ca(2+)-dependent step of activation. This is clear evidence for the occurrence of a significant conformational change in the protein structure attendant to the process of unmasking of its enzymic activity.

Selective cytotoxicity of low-density lipoprotein to helper T cells of cutaneous T-cell lymphoma after photoperoxidation with 8-methoxypsoralen.

Lymphocyte-containing plasma subjected to photolysis in the presence of 8-methoxypsoralen (methoxsalen, 8-MOP) has previously been shown to be effective against cutaneous T-cell lymphoma and the AIDS-related complex. The mechanism of this effect was thought to involve photoreaction of 8-MOP with DNA, based on certain in vitro experiments. The results of this study suggest a different mechanism. Low-density lipoprotein (LDL) from fresh human plasma was photosensitized by addition of 8-MOP and exposure to UV light (mp-LDL), and the reactions of the LDL lipids and the chemical actions induced by these reactions were monitored. In a separate procedure, LDL was peroxidized with hydrogen peroxide and peroxidase (p-LDL). mp-LDL and p-LDL were then tested in cytotoxicity assays on HuT-78 helper T cells of cutaneous T-cell lymphoma. These results indicate that (a) LDL in plasma in the presence of very low concentrations of 8-MOP (200 ng/mL) can be peroxidized by UV light; (b) this photoperoxidized LDL is cytotoxic to helper T cells of cutaneous T-cell lymphoma in a dose-dependent manner; but (c) it does not kill normal lymphocytes under similar conditions. The findings also suggest alternative therapeutic strategies for treatment of cutaneous T-cell lymphoma, such as direct utilization of peroxidized LDL.

Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas.

Radiolabeled guinea pig fibrinogen (GPF) was used to measure fibrinogen influx and fibrin accumulation in line 1 and line 10 hepato- (bile duct) carcinomas growing in the s.c. space of syngeneic strain 2 guinea pigs over the course of 7 days following transplant, an interval of growth uncomplicated by immunological tumor rejection or by significant tumor necrosis. Earlier immunofluorescence studies revealed fibrin deposits in both tumors with line 1 much greater than line 10. In accord with these data, GPF accumulated in both tumors in amounts that matched or exceeded plasma fibrinogen levels. Line 1 tumor GPF content was 4-fold greater than that of line 10 tumors and 11- to 33-fold that of normal s.c. tissue. The composition of tumor fibrinogen-fibrin was investigated by aqueous and urea extraction. The fraction of total accumulated GPF that was urea insoluble, and therefore presumably cross-linked fibrin, was constant over time but strikingly different for line 1 (65%) and line 10 (48%) tumors, as compared with control s.c. tissue (18%). By 7 days, line 1 tumors (mean weight, 0.77 g) contained nearly 2 mg of fibrinogen-fibrin, and line 10 tumors (mean weight, 0.62 g) contained nearly 0.5 mg. Influx of GPF and initial clotting were constant over time and equivalent for the two tumors. Hence, the large differences in GPF accumulation observed between these tumors apparently reflect differences in fibrinolysis, not in fibrinogen influx or coagulation. The data presented indicate substantial traffic of plasma fibrinogen into and out of both tumors, as compared with control tissues, equivalent to nearly 10 and 7 ml of plasma over 7 days of growth for line 1 and line 10 tumors, respectively; comparable values for normal s.c. tissues were 1.0 to 1.4 ml plasma fibrinogen. Even in line 1 tumors with their abundant fibrin gel, only 6.3% of GPF entering tumors over 7 days was retained, as compared with 2% for line 10 tumors and approximately 1% for control tissue.

"Sometimes I feel like a pharmacist": identity and medication use among adolescents with juvenile arthritis.

BACKGROUND: Taking medicines as intended is difficult for everybody, but young people going through adolescence have greater problems than adults and younger children. One of the most important things that happen during the teenage years is the development of individual identities, which might not remain constant during this time and can be affected deeply by the diagnosis of a long-term condition. The aim of this study was to examine the relationships between identity and medication use among young people with juvenile arthritis. METHODS: A prospective qualitative study was undertaken to collect private online 'blog' style data from young people (aged 11-19 years) with juvenile arthritis, and their parents, to examine their views about their condition, identity, medication and use of health services. Participants were identified from a large paediatric hospital in the UK. RESULTS: Young people (n = 21) with a median age 14 years (range 11-17 years) posted a median (range) of 8 (1-36) blogs and parents (n = 6) posted 4 (1-12) blogs. Young people gave a strong sense of both private and public identity that was intertwined with their arthritis and treatment. It was evident that young people's self-care was intrinsically linked to their attempts to maintain a sense of individually and socially constructed definitions of normality. The act of taking medication, and the consequences (positive or negative) of that act, had an impact both personally and socially. CONCLUSIONS: Young people with juvenile arthritis reflect on their medication as a factor affecting their perception of themselves. Acknowledging the roles of both personal and social identity will be important in any strategies to support optimal medication use. This includes an understanding of the identity transformations that young people can experience and how decision-making may be affected by their attempts to retain pre-diagnosis identities and/or develop new social identities.

Fibrinogen-sepharose interaction with prothrombin, prethrombin 1, prethrombin 2 and thrombin.

Binding of prothrombin, prethrombin 1, prethrombin 2 and thrombin to fibrinogen-Sepharose was studied. Thrombin and prethrombin 2 bound to fibrinogen-Sepharose, while prethrombin 1 and prothrombin did not. Bound thrombin and prethrombin 2 were recovered from the column by eluting with 0.1 M NaCl/0.05 M Tris-HCl buffer (pH 7.4). The affinity of thrombin and prethrombin 2 to fibrinogen-Sepharose depended on ionic strength and reached a maximum at 50 mm concentration. Prethrombin 2 interacts with fibrinogen as well as thrombin; and prothrombin fragment 1.2 is not important in the formation of this complex. Thus, prethrombin 2, which is a precursor of thrombin without measurable enzymatic activity and which lacks the single cleavage at Arg-322-Ile-323 present in thrombin, has the same or very similar structural conformation as thrombin and has the same macromolecular substrate recognition site. These results confirm the earlier results that active center is not necessary in fibrinogen-thrombin interaction.

Resistance of factor XIII to degradation or activation by plasmin.

The effect of plasmin on the subunit polypeptides of factor XIII has been investigated. purified human plasma (a2b2) and platelet (a2) zymogens and the enzyme (a2) were incubated with plasmin at plasmin: factor XIII ratios of 0.03-0.5 casein units per mg protein. Under conditions in which plasmin readily digested fibrinogen and casein, it had no effect on either a2b2 or a2. There was no evidence for cleavage of peptide bonds in the zymogens, and all the potential catalytic activity was retained after prolonged incubation. Similarly a2*, either in the presence or absence of b subunit, was also unaffected by plasmin incubation. 90% of the activity was recovered after incubation of factor XIII with plasmin. b subunit was also not degraded. Additionally, no evidence was obtained that plasmin could activate factor Xiii. These results indicate that in purified systems there is no significant interaction between plasmin and factor XIII.

Biosynthesis of plasma factor XIII: evidence for transcription and translation in hepatoma cells.

Factor XIIIa belongs to a family of ubiquitous transglutaminases, which catalyze formation of covalent bonds between the epsilon-amino group of specific lysines and the gamma-carboxyl group of glutamines. Factor XIII is synthesized as a zymogen and after activation, it participates in both the coagulation and fibrinolytic mechanisms. Most transglutaminases are intracellular, but factor XIII is both intracellular and extracellular. the biosynthesis of extracellular (plasma) factor XIII, with the structure of a noncovalent heterotetramer, A2B2, is complex. Here, evidence is presented from PCR analysis and Northern blotting that mRNAs for both A and B subunits are present in the liver. The distribution of mRNA, specific for factor XIII subunits, in various human tissues was also analyzed. Among the tissues examined, the only signal for B subunit was found in the liver. For subunit A, the signal was observed in placenta, liver, kidney, lung, skeletal muscle and heart with varying intensities; in brain or pancreas there was no signal. With an immunoperoxidase method, factor XIII A subunit was identified in the PLC/PRF/5 cell line. By ELISA and reverse immunoblotting, with antibodies specific for the A-B complex, it was also shown that these cells produce and secrete factor XIII. From all of these results, we conclude that the liver is a source of plasma factor XIII, and that the complex A2B2 is secreted from these cells.

Physical characterization of recombinant tissue plasminogen activator.

Electron microscopic and physical-chemical properties of one- and two-chain tissue plasminogen activator (t-PA) were studied. The molecular weight of one-chain t-PA obtained by both sedimentation equilibrium and SDS-PAGE was estimated to be about 65,000, while both chains in the reduced two-chain form were in the range of 35,000-40,000. Sedimentation coefficients were identical for both forms of t-PA (S(0)20,w = 4.12). The two forms of t-PA were indistinguishable by electron microscopic analysis, which confirmed the sedimentation results, and showed that they were ellipsoidal and relatively compact. The major and minor axes were approx. 13 nm and approx. 10 nm and f/f0 was 1.36. The individual domains of t-PA are relatively small and are folded within the molecule, so that the overall appearance is globular.