Search

Introduction This project developed and analysed the impact of a ward round pro forma across three wards of a large tertiary hospital containing positive or high-risk COVID-19 patients. [...]pertinent information might be missed and patient care may suffer due to incomplete records. The primary aim was to increase the amount of information documented during ward rounds (20% increase in number of parameters) and increase junior doctor confidence in documenting (1 Likert point).

Objectives. We conducted a literature review and environmental scan to develop a framework for interventions that utilize linkages between clinical practices and community organizations for the delivery of preventive services, and to identify and characterize these efforts. Methods. We searched 4 major health services and social science electronic databases and conducted an Internet search to identify examples of linkage interventions in the areas of tobacco cessation, obesity, nutrition, and physical activity. Results. We identified 49 interventions, of which 18 examples described their evaluation methods or reported any intervention outcomes. Few conducted evaluations that were rigorous enough to capture changes in intermediate or long-term health outcomes. Outcomes in these evaluations were primarily patient-focused and did not include organizational or linkage characteristics. Conclusions. An attractive option to increase the delivery of preventive services is to link primary care practices to community organizations; evidence is not yet conclusive, however, that such linkage interventions are effective. Findings provide recommendations to researchers and organizations that fund research, and call for a framework and metrics to study linkage interventions.

Context A literature review and environmental scan were conducted to develop a framework for interventions that utilize linkages between clinical practices and community organizations for the delivery of preventive services, and to identify and characterize these efforts. Evidence acquistion A search was made of four major health services and social science electronic databases and an Internet search was conducted to identify examples of linkage interventions in the areas of tobacco cessation, obesity, nutrition, and physical activity. Evidence synthesis In all, 49 interventions were identified, of which 18 examples described their evaluation methods or reported any intervention outcomes. Few conducted evaluations that were rigorous enough to capture changes in intermediate or long-term health outcomes. Outcomes in these evaluations were primarily patient-focused and did not include organizational or linkage characteristics. Conclusions An attractive option to increase the delivery of preventive services is to link primary care practices to community organizations; evidence is not yet conclusive, however, that such linkage interventions are effective. Findings provide recommendations to researchers and organizations that fund research, and call for a framework and metrics to study linkage interventions.

State health departments funded by the Centers for Disease Control and Prevention’s Nutrition, Physical Activity, and Obesity Program collaborate with multiple partners to develop and implement comprehensive obesity prevention and control programs. A mixed-methods evaluation of 28 state programs over a 5-year period assessed states’ progress on program requirements, including developing statewide partnerships and coordinating with partners to support obesity prevention and control efforts. States with greater partnership involvement leveraged more funding support for their programs, passed more obesity-related policies, and were more likely to implement obesity interventions in multiple settings. Case studies provided guidance for establishing and maintaining strong partnerships. Findings from this study offer emerging evidence to support assumptions about the centrality of partnerships to states’ success in obesity program development and implementation and related health promotion activities.

BACKGROUND: Various studies have reported a prevalence of polycystic ovaries (PCO) of ∼20% in the ‘normal’ population. Our aim was to investigate the frequency of ovulation and pattern of luteal phase progesterone secretion in a group of women with PCO who reported regular cycles and in whom ovulation had been established on the basis of previous investigations. METHODS: Subjects collected early morning urine samples for pregnanediol-3glucuronide measurement from day 10 of the cycle to day 1 of their next menses. Results in three consecutive cycles from women with PCO (group 1, n 10 and 29 for patients and cycles respectively) were compared with results from two groups with normal ovaries; with either infertility (group 2, n 10 and 30) or proven fertility (group 3, n 6 and 19). RESULTS: There were considerable variations in cycle length. The median (range) was group 1: 28 (23–47); group 2: 26 (21–36) and group 3: 27 (25–38) days with more short cycles in both infertile groups. There was more variation in pregnanediol:creatinine in the normal-ovary infertile and PCO groups than in the fertile controls. Levels were higher in the early luteal phase in the fertile normal group than in either infertile group, and the mid-luteal phase peak was lower in the infertile women with normal ovaries. In summary, there was greater variability in luteal phase pregnanediol:creatinine ratios in the PCO and infertile normal-ovary groups than in women with normal ovaries and proven fertility. CONCLUSION: Women with PCO did not have more variation in cycle length than fertile women with normal ovaries, but there were significantly lower levels of progesterone in the early luteal phase. This may contribute to the delay in conception in these patients.

Mitochondrial transfer of electrons from NAD(P)H or FADH2 to the terminal electron acceptor, oxygen, follows a highly complex scheme, involving numerous redox components. Whilst electron transfer has been extensively studied over past decades in mammalian, plant and some fungal species, relatively little is known about the respiratory chain of phytopathogenic fungi. The recent identification of the electron transport chain as a viable target for effective control of fungal infections has contributed to a significantly increased research effort into this area of fungal biochemistry. A striking feature of the electron transport chain within phytopathogenic fungi is the presence of components not found in the classical (mammalian) chain. Recent research has suggested the presence of a plant-like ‘alternative’ oxidase, internal and external NAD(P)H dehydrogenases, and cyanide-insensitive cytochrome c oxidases. In this mini-review on electron transport in phytopathogenic fungi, the current status of research into the function and expression characteristics of these ‘alternative’ redox centres is discussed. © 2000 Society of Chemical Industry

This summary describes a functional role for the alternative respiratory pathway of the wheat ‘take-all’ fungus, Gaeumannomyces graminis var tritici (Ggt), which utilises the alternative oxidase as its terminal oxidase. Unlike other plant and fungal alternative oxidases, the alternative oxidase of Ggt is both constitutively expressed and active. We have demonstrated that for cellular respiration, and therefore for ATP synthesis, to occur both the cytochrome and alternative pathways must remain active. © 1999 Society of Chemical Industry

We report here a biochemical study of resistance to azole antifungal agents in a field isolate (S-27) of a fungal phytopathogen. Isolates of Septoria tritici were compared in vitro, and their responses reflected that observed in the field, with S-27 exhibiting resistance relative to RL2. In untreated cultures, both RL2 and S-27 contained isomers of ergosterol and ergosta-5,7-dienol, although in differing concentrations. Under azole treatment, this phytopathogen exhibited a response similar to that of other pathogenic fungi, with a reduction in desmethyl sterols and an accumulation of 14(alpha)-methyl sterols, indicative of inhibition of the P450-mediating sterol 14(alpha)-demethylase. Growth arrest was attributed to the reduction of ergosterol combined with an accumulation of nonutilizable sterols. Strain S-27 exhibited an azole-resistant phenotype which was correlated with decreased cellular content of azole.

Resistance to azole fungicides in Ustilago maydis (DC) Corda has been examined using the mutant erg 40, a newly isolated mutant Tri R-1 and erg 40 revertants. Azole-induced growth arrest of the wild type did not support an obvious role for 3,6-diol in the mode of action has is clear for Saccharomyces cerevisiae Meyer ex Hansen. The level of microsomal P450 of erg 40 was identical to that of the parent, and reversion analysis showed no evidence of mutation in the sterol Δ 5(6) desaturase, as would be expected for a S. cerevisiae mutant accumulating 14α-methylfecosterol. Resistance appeared to be due to a single mutation in P450 14αdm. It is proposed that the orthologous forms of fungal sterol Δ 5(6) desaturases have varied responses when attempting to utilise 14α-methylated substrates

The storage tissues of many plants contain protease inhibitors that are believed to play an important role in defending the plant from invasion by pests and pathogens. These proteinaceous inhibitor molecules belong to a number of structurally distinct families. We describe here the isolation, purification, initial inhibitory properties, and three-dimensional structure of a novel trypsin inhibitor from seeds of Veronica hederifolia (VhTI). The VhTI peptide inhibits trypsin with a submicromolar apparent K(i) and is expected to be specific for trypsin-like serine proteases. VhTI differs dramatically in structure from all previously described families of trypsin inhibitors, consisting of a helix-turn-helix motif, with the two alpha helices tightly associated by two disulfide bonds. Unusually, the crystallized complex is in the form of a stabilized acyl-enzyme intermediate with the scissile bond of the VhTI inhibitor cleaved and the resulting N-terminal portion of the inhibitor remaining attached to the trypsin catalytic serine 195 by an ester bond. A synthetic, truncated version of the VhTI peptide has also been produced and co-crystallized with trypsin but, surprisingly, is seen to be uncleaved and consequently forms a noncovalent complex with trypsin. The VhTI peptide shows that effective enzyme inhibitors can be constructed from simple helical motifs and provides a new scaffold on which to base the design of novel serine protease inhibitors.

Malaria caused by Plasmodium vivax is a major cause of global morbidity and, in rare cases, mortality. Lactate dehydrogenase is an essential Plasmodium protein and, therefore, a potential antimalarial drug target. Ideally, drugs directed against this target would be effective against both major species of Plasmodium, P. falciparum and P. vivax. In this study, the crystal structure of the lactate dehydrogenase protein from P. vivax has been solved and is compared to the equivalent structure from the P. falciparum enzyme. The active sites and cofactor binding pockets of both enzymes are found to be highly similar and differentiate these enzymes from their human counterparts. These structures suggest effective inhibition of both enzymes should be readily achievable with a common inhibitor. The crystal structures of both enzymes have also been solved in complex with the synthetic cofactor APADH. The unusual cofactor binding site in these Plasmodium enzymes is found to readily accommodate both NADH and APADH, explaining why the Plasmodium enzymes retain enzymatic activity in the presence of this synthetic cofactor.

Amphotericin B resistant mutants of Cryptococcus neoformans were isolated accumulating mainly ergosterol. Cross-resistance to azole antifungals was not observed. Together with previous data this indicates that at least three categories of amphotericin B resistance can arise: sterol mutants, amphotericin B and azole cross-resistant mutants and amphotericin B resistant mutants with no azole cross-resistance.

This article describes the first detailed analysis of mitochondrial electron transfer and oxidative phosphorylation in the pathogenic filamentous fungus, Gaeumannomyces graminis var. tritici, While oxygen consumption was cyanide insensitive, inhibition occurred following treatment with complex III inhibitors and the alternative oxidase inhibitor, salicylhydroxamic acid (SHAM). Similarly, maintenance of a Delta psi across the mitochondrial inner membrane was unaffected by cyanide but sensitive to antimycin A and SHAM when succinate was added as the respiratory substrate. As a result, ATP synthesis through complex V was demonstrated to be sensitive to these two inhibitors but not to cyanide, Analysis of the cytochrome content of mitochondria indicated the presence of those cytochromes normally associated with electron transport in eukaryotic mitochondria together with a third, b-type heme, exhibiting a dithionite-reduced absorbance maxima at 560 nm and not associated with complex III. Antibodies raised to plant alternative oxidase detected the presence of both the monomeric and dimeric forms of this oxidase, Overall this study demonstrates that a novel respiratory chain utilizing the terminal oxidases, cytochrome c oxidase and alternative oxidase, are present and constitutively active in electron transfer in G. graminis tritici, These results are discussed in relation to current understanding of fungal electron transfer and to the possible contribution of alternative redox centers in ATP synthesis

This paper reviews the current status of our understanding of azole antifungal resistance mechanisms at the molecular level and explores their implications. Extensive biochemical studies have highlighted a significant diversity in mechanisms conferring resistance to azoles, which include alterations in sterol biosynthesis, target site, uptake and efflux. In stark contrast, few examples document the molecular basis of azole resistance. Those that do refer almost exclusively to mechanisms in laboratory mutants, with the exception of the role of multi-drug resistance proteins in clinical isolates of Candida albicans. It is clear that the technologies required to examine and define azole resistance mechanisms at the molecular level exist, but research appears distinctly lacking in this most important area.

Two amphotericin B resistant mutants of Ustilago maydis were isolated following direct selection from a wild-type population. Each mutant was demonstrated to be cross-resistant to nystatin yet remained sensitive to azoles. Sterol analysis indicated a sterol profile similar to the parent strain, precluding the involvement of an alteration in ergosterol biosynthesis as the cause of polyene resistance.

Amphotericin B resistant mutants of Cryptococcus neoformans were isolated accumulating mainly ergosterol. Cross-resistance to azole antifungals was not observed. Together with previous data this indicates that at least three categories of amphotericin B resistance can arise: sterol mutants, amphotericin B and azole cross-resistant mutants and amphotericin B resistant mutants with no azole cross-resistance.

Fluconazole was observed to inhibit sterol 14 alpha-demethylase in the human pathogen Cryptococcus neoformans, and accumulation of a ketosteroid product was associated with growth arrest. A novel mechanism(s) of azole and amphotericin B cross-resistance was identified, unrelated to changes in sterol biosynthesis, as previously identified in Saccharomyces cerevisiae. Reduced cellular content of drug could account for the resistance phenotype, indicating the possible involvement of a mechanism similar to multidrug resistance observed in higher eukaryotes.

Azole antifungals inhibit CYP51A1-mediated sterol 14α-demethylation and the mechanism(s) of resistance to such compounds in Ustilago maydis were examined. The inhibition of growth was correlated with the accumulation of the substrate, 24-methylene-24,25-dihydrolanosterol (eburicol), and depletion of ergosterol. Mutants overcoming the effect of azole antifungal treatment exhibited a unique phenotype with leaky CYP51A1 activity which was resistant to inhibition. The results demonstrate that alterations at the level of inhibitor binding to the target site can produce azole resistance. Similar changes may account for fungal azole resistance phenomena in agriculture, and also in medicine where resistance has become a problem in immuno-compromised patients suffering from AIDS.