Long-term efficacy of novel therapies in moderate-to-severe plaque psoriasis: a systematic review and network meta-analysis of PASI response.

BACKGROUND: Patients with moderate-to-severe psoriasis require long-term treatment, yet few trials compare outcomes beyond a short-term induction period. Quantitative comparisons of long-term outcomes in patients with psoriasis are limited. To our knowledge, no network meta-analysis (NMA) of such data has been performed. OBJECTIVE: To compare novel systemic therapies, both biologic and non-biologic, approved for moderate-to-severe psoriasis by conducting a systematic review (SR) and NMA of Psoriasis Area and Severity Index (PASI) outcomes measured at or around 1 year. METHODS: An SR was conducted to identify studies reporting PASI 75, PASI 90 and PASI 100 responses. Feasibility of an NMA on maintenance phase endpoints was assessed and sources of heterogeneity considered. Data appropriate for analysis were modelled using a Bayesian multinomial likelihood model with probit link. Wherever possible, data corresponding to an intention-to-treat approach with non-responder imputation were used. RESULTS: Twenty-four studies reporting outcomes at 40-64 weeks were identified, but heterogeneity in study design allowed synthesis of only 17. Four 52-week randomized controlled trials (RCTs) comprised the primary analysis, which found brodalumab was significantly more efficacious than secukinumab, ustekinumab and etanercept. Secukinumab was also more efficacious than ustekinumab and both outperformed etanercept. In a secondary analysis, evidence from 13 additional studies and 4 further therapies (adalimumab, apremilast, infliximab and ixekizumab) was included by comparing long-term outcomes from active interventions to placebo outcomes extrapolated from induction. Results were consistent with the primary analysis: brodalumab was most effective, followed by ixekizumab and secukinumab, then ustekinumab, infliximab and adalimumab. Etanercept and apremilast had the lowest expected long-term efficacy. Results were similar when studies with low prior exposure to biological therapies were excluded. CONCLUSION: Results suggest that brodalumab is associated with a higher likelihood of sustained PASI response, including complete clearance, at week 52 than comparators. Further long-term active-comparator RCT data are required to better assess relative efficacy across therapies.

Experiencing transitions: an emerging middle-range theory.

Changes in health and illness of individuals create a process of transition, and clients in transition tend to be more vulnerable to risks that may in turn affect their health. Uncovering these risks may be enhanced by understanding the transition process. As a central concept of nursing, transition has been analyzed, its components identified, and a framework to articulate and to reflect the relationship between these components has been defined. In this article, the previous conceptual analysis of transitions is extended and refined by drawing on the results of five different research studies that have examined transitions using an integrative approach to theory development. The emerging middle-range theory of transitions consists of types and patterns of transitions, properties of transition experiences, facilitating and inhibiting conditions, process indicators, outcome indicators, and nursing therapeutics. The diversity, complexity, and multiple dimensionality of transition experiences need to be further explored and incorporated in future research and nursing practice related to transitions.

Engaged mothering: the transition to motherhood for a group of African American women.

Using grounded theory methodology, 17 first-time African American mothers were interviewed to elicit their experiences of pregnancy and motherhood. Participants had a mean age of 30 years, were mostly married, employed, middle income, college educated, and all received adequate prenatal care. Engaged Mothering was identified as the core category, denoting the active, involved, and mutual process in which a woman prepares to be a mother, cares for herself and her infant, and dreams about and plans for the future to have a good life for her child. Strategies women used in this process included getting ready, dealing with the reality, settling in, and dreaming. Conditions of intentionality of the pregnancy and prior history of miscarriage or health problems of the mother affected the process. Women described the effects of racism on their daily lives and on the criteria they used to choose providers. Nursing interventions are proposed based on these results.

Nursing code of ethics: an international comparison.

In her worldwide search for a code of ethics to provide guidelines for professional practice, Linda Sawyer found that the codes of health care professionals were disappointing, mainly because they did not provide thoughtful and provocative discussion of the bioethical issues faced by the practitioner. Many organizations deal with controversial issues through the informal mechanism of policy statements, rather than through the more formal, rigid, public and political process needed to amend a code of ethics. While other professional organizations focus on commercial aspects of practice or are silent on ethical issues. Below, an analysis of the codes of selected national nurses' associations.

Chondrogenesis in the mutant nanomelia. Changes in the fine structure and proteoglycan synthesis in high density limb bud cell cultures.

High density limb bud micromass cultures, derived from individual four-day embryos, were established in order to examine chondrogenesis in normal and nanomelic embryos. One- and three-day cultures revealed no morphological differences between the two genotypes. At six days in culture, the scalloping of the cell surface observed in normal chondrocytes is not extensive in the mutant, and the extracellular matrix granules are greatly reduced in number. Differences in sulfated proteoglycan (PGS) synthesis were first detected at three days in culture when the mutant failed to synthesize cartilage-specific PGS. The study, therefore, indicates that the mutant gene is not expressed in prechondrogenic cells.

Chondrogenesis in chick limb mesenchyme in vitro derived from distal limb bud tips: changes in cyclic AMP and in prostaglandin responsiveness.

Chondrogenesis was monitored in micromass cultures of mesenchymal cells derived from the distal tip of stage-25 chick limb buds over a 6-day period. Alcian green staining and immunofluorescent localization of cartilage-specific proteoglycans revealed the appearance of cartilage matrix by day 3 of cell culture. By day 6, cultures contained a uniform and homogeneous population of fully differentiated chondrocytes throughout the cell layer, with only a narrow rim of nonchondrogenic cells around the extreme periphery of the culture. Synthesis of sulfated glycosaminoglycans also progressively increased between days 3 and 6, being 8-fold higher at day 6 than at day 1 of culture. Both adenylate cyclase (AC) activity and cAMP concentrations increased dramatically during the first 2 days of culture, reaching maximal levels by day 2, which remained elevated and stable throughout the remaining chondrogenic period (days 3-6). Responsiveness of both AC and cAMP concentrations of the cells to PGE2 was maximal by day 1 of culture and was increased over control cells by 12-fold and 8-fold respectively. Both responses, however, were dramatically reduced by day 3, at which time the initiation of cartilage formation was apparent. Responsiveness of cells during the prechondrogenic period to PGE2 was relatively specific in that no effects could be demonstrated with equivalent concentrations of PGF2 alpha or 6-keto-PGF1 alpha, although PGl2 did produce increases in cAMP concentrations of about 50% of those of PGE2. These results indicate that previously reported changes in the cAMP system in heterogeneous cell cultures derived from whole limb buds reflect changes occurring in the chondrogenic cell type and indicate further that peak responsiveness of the cAMP system of these cells to prostaglandins is restricted to prechondrogenic developmental periods.

Chondrogenesis of chick limb mesenchyme in vitro. Effects of prostaglandins on cyclic AMP.

The effects of prostaglandin E2 (PGE2) on cyclic AMP (cAMP) levels of chick limb bud cells during various stages of chondrogenesis were studied utilizing high density, micro-mass, cell culture. Concentrations of PGE2 in cell cultures at these same stages were measured by radio-immunoassay. Both basal levels of cAMP, as well as PGE2-stimulated changes in cAMP, increased maximally during the first 3 days of culture; this increase was associated with the formation of cell aggregates. Concentrations of PGE2 were also highest during this period. By 6 days of culture, nodules, containing cartilage matrix components, predominated. Both basal levels of cAMP and PGE2-stimulated cAMP levels were significantly decreased at this stage, relative to cultures at day 3. Concentrations of PGE2 fell dramatically in the 6-day cultures containing differentiated cartilage. These results support a regulatory role for both PGE2 and cAMP in the early events associated with chondrogenesis.

Inhibition of chondrogenesis by retinoic acid in limb mesenchymal cells in vitro: effects on PGE2 and cyclic AMP concentrations.

Effects of retinoic acid (RA) on prostaglandin E2 (PGE2) and cyclic AMP (cAMP) concentrations were investigated in high density, micromass cultures of mesenchymal cells derived from chick limb buds. Exposure of cells during the initial 24 h of culture to RA concentrations between 0.05-1.0 micrograms/ml inhibited chondrogenesis in a dose-dependent manner with 1.0 micrograms/ml totally inhibiting cartilage formation. Concentrations of PGE2 and cAMP increased during the prechondrogenic period in control cells in a closely related way and remained elevated throughout the six-day period examined. Addition of RA (0.05 and 0.5 micrograms/ml) did not significantly alter cAMP concentrations at any time point, but significantly elevated PGE2 levels relative to control cells in six-day cultures in a concentration-dependent manner. Addition of dibutyryl cAMP enhanced chondrogenesis in control cells between days 3 and 4, but failed to alter the inhibitory effect of RA on chondrogenesis. The results indicate that while PGE2 and cAMP are important signals in cartilage differentiation, the inhibitory effects of RA on this process are mediated through some other mechanism.

Immunolocalization of proteoglycan types in aortas of pigeons with spontaneous or diet-induced atherosclerosis.

The location of different proteoglycan (PG) types in the developing atherosclerotic lesion was examined by the use of monoclonal antibodies directed toward specific epitopes on distinct PG types. Sections of aorta were prepared from young White Carneau pigeons fed an atherogenic diet to induce lesions rich in lipid-laden macrophages and from older pigeons that had naturally-occurring atherosclerotic lesions. Monoclonal antibodies (MAb) 3-B-3, 9-A-2, or 2-B-6 and 5-D-4, recognizing delta Di-6S generated from chondroitin 6-sulfate (C6S) PG; delta Di-4S generated from dermatan sulfate (DS) PG and from chondroitin 4-sulfate (C4S); and sulfated poly N-acetyllactosamine sequences common to keratan sulfate (KS), respectively, were used to localize PG types by indirect immunofluorescence. In normal aorta, C6S PG was localized primarily in the media and showed a fluorescent gradient (inner media greater than outer media greater than intima greater than adventitia). In the atherosclerotic plaque, major immunoreactivity was observed using MAb 9-A-2 or 2-B-6, whereas lesser amounts were observed with 3-B-3. Patterns of immunoreactivity differed; 9-A-2 or 2-B-6 appeared to be associated with cells whereas 3-B-3 appeared to be intercellular. Although normal aorta was negative for antibody 5-D-4, recognizing KS, atherosclerotic plaques were consistently positive for this antibody. The pattern of 5-D-4 reactivity appeared to be intercellular. Except for immediately below the lesion, no reactive product using 5-D-4 was observed in the media. No major differences in distribution of PG were observed between naturally-occurring or cholesterol-induced fibrous plaques. These results indicate that both 4-sulfated PG and a previously undescribed KS glycoconjugate are major components of the atherosclerotic lesion.

Mesenchymal-epithelial interactions in sex differentiation.

Development of male and female accessory sexual glands is described in terms of the respective roles of epithelium and mesenchyme. During embryonic and neonatal periods mesenchyme alone exhibits androgen receptor activity (nuclear androgen binding sites) and is the actual target and mediator of the morphogenetic effects of androgens upon the epithelium. Mesenchyme induces specific patterns of epithelial morphogenesis, cytodifferentiation, and probably also specifies the functional (biochemical) activities of the epithelium. Mesenchymal influence upon expression of epithelial characteristics occurs in the perinatal period during morphogenesis, but also plays an important role in adulthood by maintaining favorable conditions for maintenance of epithelial morphology and function. Morphogenetic processes in adult hormone-dependent organs are though to be mediated by stromal cells.