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Over the last decade the National Health Service (NHS) in the United Kingdom has experienced major organizational change. Successive government initiatives designed to improve local management of hospitals have tended to marginalize nurses. Resource Management, a major initiative, which is the model adopted in the NHS Review for hospital management for the 1990s, appeared initially to offer nurses an opportunity to influence decision-making directly. In practice, nurses' experiences of Resource Management were mixed. This study of the six hospitals which piloted the introduction of Resource Management showed that nurses did not always grasp the opportunity to enhance their power and practice. There was evidence from the study that the introduction of information technology curbed innovations in practice, and removed nurses from patient care delivery. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to review the impact of the clinical leadership programme, in enabling the Darzi fellows to lead change projects in health and care services, and to secure quality healthcare in the NHS beyond the lifetime of the programme., Design/methodology/approach: A longitudinal empirical investigation of clinical leaders ( n=80) over an eight-year period was framed through an activity theory (AT)-driven research methodology using a mixed-methods approach., Findings: AT illuminated how change was sustained in the NHS in London through the Darzi Clinical Leadership Fellowship. By any reasonable measurement, this programme excels, with learning and positive behavioural change sustained after the Fellowship across the NHS. Further recognition is needed of the continuing development needs of fellows as they take on more responsible leadership roles in their careers., Research Limitations/implications: Darzi fellows are a hard-to-reach group. The sample represents a response rate of 34 per cent. In total, 77 per cent of respondents emanated from cohorts 5 to 8 programmes., Practical Implications: The investment in a clinical leadership programme focused on systems leadership for quality generates value for the NHS., Social Implications: Countless interventions flowed through London's healthcare community and beyond as a result of the Fellowship. This research exposed how Darzi fellows continue to lead innovation for alternative healthcare outcomes. Many proactive fellows employ a suite of learned skills and capabilities to lead systemic change., Originality/value: This research is the first known longitudinal clinical leadership development study undertaken. The Darzi programme has created a unique clinical network of mutually supportive, team-centric systems thinkers and doers, with an evidence-based approach to systems change. Many fellows are catalysing sustainable change in the healthcare environment.

In this implementation phase of the European Cancer Patient's Bill of Rights (BoR), we confirm the following three patient-centred principles that underpin this initiative:The right of every European citizen to receive the most accurate information and to be proactively involved in his/her care.The right of every European citizen to optimal and timely access to a diagnosis and to appropriate specialised care, underpinned by research and innovation.The right of every European citizen to receive care in health systems that ensure the best possible cancer prevention, the earliest possible diagnosis of their cancer, improved outcomes, patient rehabilitation, best quality of life and affordable health care. The key aspects of working towards implementing the BoR are:Agree our high-level goal. The vision of 70% long-term survival for patients with cancer in 2035, promoting cancer prevention and cancer control and the associated progress in ensuring good patient experience and quality of life.Establish the major mechanisms to underpin its delivery. (1) The systematic and rigorous sharing of best practice between and across European cancer healthcare systems and (2) the active promotion of Research and Innovation focused on improving outcomes; (3) Improving access to new and established cancer care by sharing best practice in the development, approval, procurement and reimbursement of cancer diagnostic tests and treatments.Work with other organisations to bring into being a Europe based centre that will (1) systematically identify, evaluate and validate and disseminate best practice in cancer management for the different countries and regions and (2) promote Research and Innovation and its translation to maximise its impact to improve outcomes., Competing Interests: Competing interests: None declared.

The NHS Leadership Academy in England is investing £46 million in a standardized model of development, with academic qualifications becoming essential in future NHS leadership roles. This represents a cul-de-sac for medical leaders because it is based on a series of misplaced assumptions about health-care leadership and its development.

The need to develop the leadership and management capability of clinicians is deemed fundamental to address the cost and quality issues associated with health-care provision. The challenge facing the NHS is how best to bring this about.

The serine repeat antigen (SERA) proteins of the malaria parasites Plasmodium spp. contain a putative enzyme domain similar to that of papain family cysteine proteases. In Plasmodium falciparum parasites, more than half of the SERA family proteins, including the most abundantly expressed form, SERA5, have a cysteine-to-serine substitution within the putative catalytic triad of the active site. Although SERA5 is required for blood-stage parasite survival, the occurrence of a noncanonical catalytic triad casts doubt on the importance of the enzyme domain in this function. We used phage display to identify a small (14-residue) disulfide-bonded cyclic peptide (SBP1) that targets the enzyme domain of SERA5. Biochemical characterization of the interaction shows that it is dependent on the conformation of both the peptide and protein. Addition of this peptide to parasite cultures compromised development of late-stage parasites compared to that of control parasites or those incubated with equivalent amounts of the carboxymethylated peptide. This effect was similar in two different strains of P. falciparum as well as in a transgenic strain where the gene encoding the related serine-type parasitophorous vacuole protein SERA4 was deleted. In compromised parasites, the SBP1 peptide crosses both the erythrocyte and parasitophorous vacuole membranes and accumulates within the parasitophorous vacuole. In addition, both SBP1 and SERA5 were identified in the parasite cytosol, indicating that the plasma membrane of the parasite was compromised as a result of SBP1 treatment. These data implicate an important role for SERA5 in the regulation of the intraerythrocytic development of late-stage parasites and as a target for drug development.

The packaging of genomic RNA in members of the Cystoviridae is performed by P4, a hexameric protein with NTPase activity. Across family members such as Phi6, Phi8 and Phi13, the P4 proteins show low levels of sequence identity, but presumably have similar atomic structures. Initial structure-determination efforts for P4 from Phi6 and Phi8 were hampered by difficulties in obtaining crystals that gave ordered diffraction. Diffraction from crystals of full-length P4 showed a variety of disorder and anisotropy. Subsequently, crystals of Phi13 P4 were obtained which yielded well ordered diffraction to 1.7 A. Comparison of the packing arrangements of P4 hexamers in different crystal forms and analysis of the disorder provides insights into the flexibility of this family of proteins, which might be an integral part of their biological function.

The concentration of double-stranded RNA within the bluetongue virus core renders the genome segments liquid crystalline. Powder diffraction rings confirm this local ordering with a 30 A separation between strands. Determination of the structure of the bluetongue virus core serotype 10 and comparison with that of serotype 1 reveals most of the genomic double-stranded RNA, packaged as well-ordered layers surrounding putative transcription complexes at the apices of the particle. The outer layer of RNA is sufficiently well ordered by interaction with the capsid that a model can be built and extended to the less-ordered inner layers, providing a structural framework for understanding the mechanism of this complex transcriptional machine. We show that the genome segments maintain local order during transcription.

The structure of the core particle of bluetongue virus has been determined by X-ray crystallography at a resolution approaching 3.5 A. This transcriptionally active compartment, 700 A in diameter, represents the largest molecular structure determined in such detail. The atomic structure indicates how approximately 1,000 protein components self-assemble, using both the classical mechanism of quasi-equivalent contacts, which are achieved through triangulation, and a different method, which we term geometrical quasi-equivalence.

The structure of the complex between a recombinant single-chain Fv construct of antibody NC10 with a five-residue peptide linker between VH and VL (termed scFv(5)), and its antigen, tetrameric neuraminidase from influenza virus (NA), has been determined and refined at 2.5 A resolution. The antibody-antigen binding interface is very similar to that of a similar NC10 scFv-NA complex in which the scFv has a 15-residue peptide linker (scFv(15)), and the NC10 Fab-NA complex. However, scFv(5) and scFv(15) have different stoichiometries in solution. While scFv(15) is predominantly monomeric in solution, scFv(5) forms dimers exclusively, because the five-residue linker is not long enough to permit VH and VL domains from the same polypeptide associating and forming an antigen-binding site. Upon forming a complex with NA, scFv(15) forms a approximately 300 kDa complex corresponding to one NA tetramer binding four scFv(15) monomers, while scFv(5) forms a approximately 590 kDa complex, corresponding to two NA tetramers crosslinked by four bivalent scFv(5) dimers. However, the dimeric scFv(5) in the scFv(5)-NA crystals does not crosslink NA tetramers, and modelling studies indicate that it is not possible to pack four dimeric and simultaneously bivalent scFvs between the NA tetramers with only a five-residue linker between VH and VL. The inability arises from the exacting requirement to orient the two antigen-binding surfaces to bind the tetrameric NA antigen while avoiding steric clashes with NC10 scFv(5) dimers bound to other sites on the NA tetramer. The utility of bivalent or bifunctional scFvs with short linkers may therefore be restricted by the steric constraints imposed by binding multivalent antigens., (Copyright 1998 Academic Press Limited.)

Nursing Development Units (NDUs) are seen as one of the most fundamental advancements in the development of nursing practice in the United Kingdom. The concept of the NDU is described, along with a history of the growth of these units, and the lessons learned along the journey.

Background: While it is well known that different antibodies can be produced against a particular antigen, and even against a particular site on an antigen, up until now there have been no structural studies of cross-reacting antibodies of this type. One antibody-antigen complex whose structure is known is that of the influenza virus antigen, neuraminidase, in complex with the NC41 antibody. Another anti-neuraminidase antibody, NC10, binds to an overlapping site on the antigen. The structure of the complex formed by this antibody with neuraminidase is described here and compared with the NC41-containing complex., Results: The crystal structure of the NC10 Fab-neuraminidase complex has been refined to a nominal resolution of 2.5A. Approximately 80% of the binding site of the NC10 antibody on neuraminidase overlaps with that of the NC41 antibody. The epitope residues of neuraminidase are often engaged in quite different interactions with the two antibodies. Although the NC10 and NC41 antibodies have identical amino acid sequences within the first complementarity determining region of their heavy chains, this is not the basis of the cross-reaction., Conclusions: The capacity of two different proteins to bind to the same target structure on a third protein need not be based on the existence of identical or homologous amino acid sequences within those proteins. As we have demonstrated, amino acid residues on the common target structure may be in quite different chemical environments, and may also adopt different conformations within two protein-protein complexes.

Background: N-acetylneuraminate lyase catalyzes the cleavage of N-acetylneuraminic acid (sialic acid) to form pyruvate and N-acetyl-D-mannosamine. The enzyme plays an important role in the regulation of sialic acid metabolism in bacteria. The reverse reaction can be exploited for the synthesis of sialic acid and some of its derivatives., Results: The structure of the enzyme from Escherichia coli has been determined to 2.2 A resolution by X-ray crystallography. The enzyme is shown to be a tetramer, in which each subunit consists of an alpha/beta-barrel domain followed by a carboxy-terminal extension of three alpha-helices., Conclusions: The active site of the enzyme is tentatively identified as a pocket at the carboxy-terminal end of the eight-stranded beta-barrel. Lys165 lies within this pocket and is probably the reactive residue which forms a Schiff base intermediate with the substrate. The sequence of N-acetylneuraminate lyase has similarities to those of dihydrodipicolinate synthase and MosA (an enzyme implicated in rhizopine synthesis) suggesting that these last two enzymes share a similar structure to N-acetylneuraminate lyase.

The single-chain antibody variable fragment (scFv), with a 15-residue polypeptide linker (Gly4Ser)3, of monoclonal antibody NC10 was expressed in Escherichia coli and purified to homogeneity. This scFv molecule, refolded from 6 M guanidine hydrochloride, was predominantly a monomer of 27 kDa and was stable on storage at 4 degrees and 20 degrees C. At higher protein concentrations (approximately 5 mg/ml) dimer and higher-molecular-mass multimers were formed and freezing enhanced this aggregation. The dimer was not stable and dissociated to monomer at 20 degrees C with a half-life of approximately 8 days. The higher-molecular-mass multimers and dimer dissociated to monomer in 60% ethylene glycol. Both the monomer and dimer were active and with tern N9 sialidase yielded complexes of 276 kDa and 569 kDa, respectively, indicating that four scFv molecules bound/sialidase tetramer and that the dimer was bivalent and cross-linked two sialidase tetramers. Binding studies at low concentrations and using radiolabelled scFv indicated that the binding affinity of the dimer was approximately twofold higher than that of the monomer, and the binding affinities of the scFv were similar to that of the parent NC10 antigen-binding fragment (Fab) molecule. A complex between tern N9 sialidase and NC10 scFv was crystallized and the structure of the complex was solved at 0.3-nm resolution by X-ray diffraction. Comparison of this scFv/sialidase structure with the parent Fab/sialidase structure revealed that the modes of attachment of scFv and Fab to sialidase were very similar. There was no discernible electron density for the peptide linker joining the variable heavy (VH) and variable light (VL) chains. A close interaction between two symmetry-related scFv suggests that they may have crystallized as dimers.

Phagemid vectors have been developed which promise to supersede hybridoma technology for the selection and production of human antibodies. We have modified an existing phagemid vector to improve the stability of synthesized soluble antibody fragments. The vector allows the antibody fragment to be produced: i) as a soluble protein incorporating a stable carboxyl terminal octapeptide (FLAG) or, ii) on the surface of a bacteriophage fused to a minor coat protein (the gene III protein). The antibody gene encoding the well characterized monoclonal antibody NC10 (an antibody that recognizes the neuraminidase of the influenza strain N9) was inserted as a single chain Fv construct into the phagemid vectors pHFA and pHFA/SacII. Western blotting, ELISA and electron microscopy studies showed that recombinant clones could be manipulated to either synthesize soluble protein into the periplasm or present the protein on the surface of bacteriophage. Cosynthesis of GroEL and GroES chaperonins resulted in complete proteolysis of the scFvNC10-FLAG-gIIIp fusion product and did not improve total phage production. Coexpression of chaperonins should be used with caution for library construction due to the expected selection pressure for protease resistant gene III fusions.

The variable heavy (VH) and variable light (VL) genes of NC10, a monoclonal antibody with specificity toward N9 neuraminidase (NA), were cloned and sequenced. A single chain Fv (scFv) fragment of NC10, consisting of VH and VL domains joined by a peptide linker, was designed, constructed and expressed in the E. coli expression vector pPOW. The N-terminal secretion signal PelB directed the synthesized protein into the periplasm where it was associated with the insoluble membrane fraction. An octapeptide (FLAG) tail was fused to the C-terminus of the single chain Fv to aid in its detection and remained intact throughout the protein purification process. NC10 scFv was purified by solubilization of the E. coli membrane fraction with guanidinium hydrochloride followed by column chromatography. The purified NC10 scFv showed binding affinity for its antigen, NA, 2-fold lower than that of the parent Fab. The complex between NA and the scFv has been crystallized by the vapor diffusion method. The crystals are tetragonal, space group P42(1)2, with unit cell dimensions a = b = 141 A, c = 218 A.

This article reviews the current literature on change in nursing audit in order to develop a strategy for nursing staff. It suggests that the model for change will affect the nature of the measurement phase of audit, and proposes that an open systems model be adopted and a change agent incorporated to manage the audit cycle.

If you want to know what's happening in England, go to Canada. There you will find out officially about anonymous HIV testing programmes, carried out here without our consent, and which the doctors have been keeping very quiet about.