Improving the quality of healthcare: a cross-sectional study of the features of successful clinical networks.

OBJECTIVES: Networks of clinical experts are being established internationally to help embed evidence based care in health systems. There is emerging evidence that these clinical networks can drive quality improvement programs, but the features that distinguish successful networks are largely unknown. We examined the factors that make clinical networks effective at improving quality of care and facilitating system-wide changes. METHODS: We conducted a retrospective cross-sectional study of 19 state-wide clinical networks that reflected a range of medical and surgical specialty care and were in operation from 2006 to 2008 in New South Wales, Australia. We conducted qualitative interviews with network leaders to characterise potential impacts, and conducted internet surveys of network members to evaluate external support and the organisational and program characteristics of their respective networks. The main outcome measures were median ratings of individual network impacts on quality of care and system-wide changes, determined through independent assessment of documented evidence by an expert panel. RESULTS: We interviewed 19 network managers and 32 network co-chairs; 592 network members completed internet surveys. Three networks were rated as having had high impact on quality of care, and seven as having had high impact on system-wide change. Better-perceived strategic and operational network management was significantly associated with higher ratings of impact on quality of care (coefficient estimate 0.86; 95% confidence interval [CI] 0.02, 1.69). Better-perceived leadership of the network manager (coefficient estimate 0.47; 95% CI 0.10, 0.85) and strategic and operational network management (coefficient estimate 0.23; 95% CI 0.06, 0.41) were associated with higher ratings of impact on system-wide change. CONCLUSIONS: This study represents the largest study of clinical networks undertaken to date. The results suggest that clinical networks that span the health system can improve quality of care and facilitate system-wide change. Network management and leadership, encompassing both strategic and operational elements at the organisational level, appear to be the primary influences on network success. These findings can guide future organisational and system-wide change programs and the development or strengthening of clinical networks to help implement evidence based care to improve service delivery and outcomes.

Selection of epitopes from self-antigens for eliciting Th2 or Th1 activity in the treatment of autoimmune disease or cancer.

Vaccines have been valuable tools in the prevention of infectious diseases, and the rapid development of new vectors against constantly mutating foreign antigens in viruses such as influenza has become a regular, seasonal exercise. Harnessing the immune response against self-antigens is not necessarily analogous or as achievable by iterative processes, and since the desired outcome includes leaving the targeted organism intact, requires some precision engineering. In vaccine-based treatment of autoimmunity and cancer, the proper selection of antigens and generation of the desired antigen-specific therapeutic immunity has been challenging. Both cases involve a threshold of existing, undesired immunity that must be overcome, and despite considerable academic and industry efforts, this challenge has proven to be largely refractory to vaccine approaches leveraging enhanced vectors, adjuvants, and administration strategies. There are in silico approaches in development for predicting the immunogenicity of self-antigen epitopes, which are being validated slowly. One simple approach showing promise is the functional screening of self-antigen epitopes for selective Th1 antitumor immunogenicity, or inversely, selective Th2 immunogenicity for treatment of autoimmune inflammation. The approach reveals the importance of confirming both Th1 and Th2 components of a vaccine immunogen; the two can confound one another if not parsed but may be used individually to modulate antigen-specific inflammation in autoimmune disease or cancer.

Th1 epitope selection for clinically effective cancer vaccines.

New cancer immunotherapies mark progress in our understanding of tumor biology and harnessing the immune system's management of self. However, protein- and peptide-based vaccines are not yet consistently efficacious. Recent work uncovers principles governing the genesis of T helper type-restrictive immunity to self-antigens elicited by vaccine epitopes, enabling vaccines to skew the balance from tolerogenic Type II (Th2) to inflammatory Type I (Th1) T cells, and invigorating this cancer immunotherapeutic approach.

Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors.

Because of their central role in programmed cell death, the caspases are attractive targets for developing new therapeutics against cancer and autoimmunity, myocardial infarction and ischemic damage, and neurodegenerative diseases. We chose to target caspase-3, an executioner caspase, and caspase-8, an initiator caspase, based on the vast amount of information linking their functions to diseases. Through a structure-based drug design approach, a number of novel beta-strand peptidomimetic compounds were synthesized. Kinetic studies of caspase-3 and caspase-8 inhibition were carried out with these urazole ring-containing irreversible peptidomimetics and a known irreversible caspase inhibitor, Z-VAD-fmk. Using a stopped-flow fluorescence assay, we were able to determine individual kinetic parameters of caspase-3 and caspase-8 inhibition by these inhibitors. Z-VAD-fmk and the peptidomimetic inhibitors inhibit caspase-3 and caspase-8 via a three-step kinetic mechanism. Inhibition of both caspase-3 and caspase-8 by Z-VAD-fmk and of caspase-3 by the peptidomimetic inhibitors proceeds via two rapid equilibrium steps followed by a relatively fast inactivation step. However, caspase-8 inhibition by the peptidomimetics goes through a rapid equilibrium step, a slow-binding reversible step, and an extremely slow inactivation step. The crystal structures of inhibitor complexes of caspases-3 and -8 validate the design of the inhibitors by illustrating in detail how they mimic peptide substrates. One of the caspase-8 structures also shows binding at a secondary, allosteric site, providing a possible route to the development of noncovalent small molecule modulators of caspase activity.

Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy.

To study effects of mitochondrial complex I (CI, NADH:ubiquinone oxidoreductase) deficiency, we inactivated the Ndufs4 gene, which encodes an 18 kDa subunit of the 45-protein CI complex. Although small, Ndufs4 knockout (KO) mice appeared healthy until approximately 5 weeks of age, when ataxic signs began, progressing to death at approximately 7 weeks. KO mice manifested encephalomyopathy including a retarded growth rate, lethargy, loss of motor skill, blindness, and elevated serum lactate. CI activity in submitochondrial particles from KO mice was undetectable by spectrophotometric assays. However, CI-driven oxygen consumption by intact tissue was about half that of controls. Native gel electrophoresis revealed reduced levels of intact CI. These data suggest that CI fails to assemble properly or is unstable without NDUFS4. KO muscle has normal morphology but low NADH dehydrogenase activity and subsarcolemmal aggregates of mitochondria. Nonetheless, total oxygen consumption and muscle ATP and phosphocreatine concentrations measured in vivo were within normal parameters.

Prostate cancer detection in men with an initial diagnosis of atypical small acinar proliferation.

OBJECTIVE: To determine the subsequent prostatic adenocarcinoma detection rate amongst men with an initial diagnosis of atypical small acinar proliferation (ASAP). PATIENTS AND METHODS: We reviewed the Illawarra Prostate Pathology Database over a 10-year period (January 1994 to January 2004) for specimens diagnosed as ASAP. These specimens were re-reviewed and clinical data obtained. RESULTS: Of 61 cases of ASAP, there were complete follow-up data for 31. In this group nine patients had no further biopsies at our institution; the other 22 had at least one repeat biopsy. The incidence of prostatic adenocarcinoma in this group was 17/31 (55%). This included 13 diagnoses on second biopsy, three on third biopsy and one diagnosed at another institution. CONCLUSION: This study showed a detection rate for prostatic adenocarcinoma of 55% after an initial diagnosis of ASAP, which indicates that an initial diagnosis of ASAP mandates re-biopsy.

Odorant stimulation enhances survival of olfactory sensory neurons via MAPK and CREB.

Olfactory sensory neurons (OSNs) can be sensitized to odorants by repeated exposure, suggesting that an animal's responsiveness to olfactory cues can be enhanced at the initial stage of detection. However, because OSNs undergo a regular cycle of apoptosis and replacement by ostensibly naive, precursor-derived neurons, the advantage of sensitization would be lost in the absence of a mechanism for odorant-enhanced survival of OSNs. Using recombinant adenoviruses in conjunction with surgical and electrophysiological techniques, we monitored OSN survival and function in vivo and find that odorant exposure selectively rescues populations of OSNs from apoptosis. We further demonstrate that odorant stimuli rescue OSNs in a cAMP-dependent manner by activating the MAPK/CREB-dependent transcriptional pathway, possibly as a result of expression of Bcl-2.

The effect of remote chirality on the antibacterial activity of indolinyl, tetrahydroquinolyl and dihydrobenzoxazinyl oxazolidinones.

The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.

Observations on the relationship between triazines and mycobacteria in metal removal fluids.

The purpose of the study was to determine whether hexahydrotriazine ("triazine") bactericides increase the likelihood of elevated mycobacteria growth in metal removal fluids (MRFs). In reaction to an outbreak of hypersensitivity pneumonitis (HP) at a transmission manufacturing facility, machining plants of a large automobile manufacturer were directed to increase the testing of MRF, especially testing for mycobacteria. A working hypothesis was developed that triazine bactericides cause an increase in mycobacteria contamination, which in turn may lead to an increased risk of HP for workers exposed to MRF aerosols. Test results for 277 central MRF systems from nine machining facilities were analyzed for various MRF properties including the presence and type of both bactericide in the MRF formula and bacterial contamination of the MRF. The study included data reflecting usual operating conditions of all of the 277 large MRF systems in the company. The study does not evaluate the effect of tank-side biocide addition. The results show that soluble oils, semi-synthetic, and synthetic MRFs are all capable of supporting mycobacterial growth. The results also demonstrate a highly significant association between routine use of triazine bactericides and mycobacterial contamination of MRF. Based on the hypothesis that mycobacteria are a likely causative agent of hypersensitivity pneumonitis from MRF exposure, it is concluded that elimination of triazines from MRF formulae may be protective against HP in the machining environment.

Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens.

A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.

Novel Asymmetric Synthesis of Atropisomeric 6-Aryl Pyrazinones via an Unusual Chirality Transfer Process.

Cyclization of (S,S)-alpha-[(1-phenylethyl)amino]-alpha-(2-iodophenyl)acetonitrile with (COCl)(2) in toluene or chlorobenzene afforded the atropisomeric pyrazinone (aS,S) 6-(2-alpha-iodophenyl)-3,5-dichloro-1-(1-phenylethyl)-2(1H)-pyrazinone in 57% yield. With smaller ortho substituents (F, Cl, CH(3), CF(3), OCH(3)) on the aromatic ring, mixtures of atropisomers were obtained from the cyclization reaction. All of the individual atropisomers prepared were stable at room temperature. All but the o-fluoro-substituted atropisomers were stable at elevated temperatures. This paper describes a stereoselective synthesis of pyrazinones and suggests a mechanism for formation via an interesting transfer of chirality.

Cyclopentene Synthesis from 1,3-Dienes via Base-Induced Ring Contraction of 3,6-Dihydro-2H-thiopyrans: Studies on Diastereoselection and Mechanism.

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the alpha-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism.