Alison Lesley Weightman

Stereospecificity of 2-Monochloropropionate Dehalogenation by the Two Dehalogenases of Pseudomonas putida PP3: Evidence for Two Different Dehalogenation Mechanisms

Pseudomonas putida PP3 grew on DL-2-monochloropropionate (2MCPA) with a release of chloride ions consistent with the dechlorination of both isomers. The organism grew on either D- or L-2MCPA. Dehalogenase activity in cell-free extracts showed that both D- and L-2MCPA were dehalogenated. Pseudomonas putida PP3 contains two dehalogenases, and studies with the separated enzymes revealed that the fraction I enzyme used both D- and L-2MCPA, the rate of dechlorination of L-2MCPA being 80% of the rate of D-2MCPA dechlorination. The product of the reaction, lactate, retained the same optical configuration as the substrate provided. The fraction II dehalogenase also dechlorinated D- and L-2MCPA, with the same difference in rates as for the fraction I dehalogenase, but the lactates produced were of the opposite configuration to their precursors. The two dehalogenases showed further differences with respect to inhibition by two sulphydryl-blocking agents, N-ethylmaleimide and p-chloromercuribenzoate. Fraction I dehalogenase was considerably more sensitive to these two reagents compared with the fraction II dehalogenase. Dithiothreitol partially protected the fraction I dehalogenase from N-ethylmaleimide inhibition. The results are discussed in terms of the possible evolutionary relationships of the two dehalogenases.

Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies.

Background Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. Objectives We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. Methods Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. Results Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79–0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76–0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. Conclusions and Implications The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. Systematic Review Protocol Number CRD42015014145

Social inequality and infant health in the UK: systematic review and meta-analyses

Objectives To determine the association between area and individual measures of social disadvantage and infant health in the UK. Design Systematic review and meta-analyses. Data sources 26 databases and websites, reference lists, experts in the field and hand-searching. Study selection 36 prospective and retrospective observational studies with socioeconomic data and health outcomes for infants in the UK, published from 1994 to May 2011. Data extraction and synthesis 2 independent reviewers assessed the methodological quality of the studies and abstracted data. Where possible, study outcomes were reported as ORs for the highest versus the lowest deprivation quintile. Results In relation to the highest versus lowest area deprivation quintiles, the odds of adverse birth outcomes were 1.81 (95% CI 1.71 to 1.92) for low birth weight, 1.67 (95% CI 1.42 to 1.96) for premature birth and 1.54 (95% CI 1.39 to 1.72) for stillbirth. For infant mortality rates, the ORs were 1.72 (95% CI 1.37 to 2.15) overall, 1.61 (95% CI 1.08 to 2.39) for neonatal and 2.31 (95% CI 2.03 to 2.64) for post-neonatal mortality. For lowest versus highest social class, the odds were 1.79 (95% CI 1.43 to 2.24) for low birth weight, 1.52 (95% CI 1.44 to 1.61) for overall infant mortality, 1.42 (95% CI 1.33 to1.51) for neonatal and 1.69 (95% CI 1.53 to 1.87) for post-neonatal mortality. There are similar patterns for other infant health outcomes with the possible exception of failure to thrive, where there is no clear association. Conclusions This review quantifies the influence of social disadvantage on infant outcomes in the UK. The magnitude of effect is similar across a range of area and individual deprivation measures and birth and mortality outcomes. Further research should explore the factors that are more proximal to mothers and infants, to help throw light on the most appropriate times to provide support and the form(s) that this support should take.

Taking STOX: developing a cross disciplinary methodology for systematic reviews of research on the built environment and the health of the public

Study objective: To develop a cross disciplinary literature search methodology for conducting systematic reviews of all types of research investigating aspects of the built environment and the health of the public. Design: The method was developed following a comprehensive search of literature in the area of housing and injuries, using 30 databases covering many disciplines including medicine, social science, architecture, science, engineering, environment, planning and psychology. The results of the database searches, including the type (or evidence) of research papers identified, were analysed to identify the most productive databases and improve the efficiency of the strategy. The revised strategy for literature searching was then applied to the area of neighbourhoods and mental health, and an analysis of the evidence type of references was carried out. In recognition of the large number and variety of observational studies, an expanded evidence type classification was developed for this purpose. Main results: From an analysis of 722 citations obtained by a housing and injuries search, an overlap of only 9% was found between medical and social science databases and only 1% between medical and built environment databases. A preliminary evidence type classification of those citations that could be assessed (from information in the abstracts and titles) suggested that the majority of intervention studies on housing and injuries are likely to be found in the medical and social science databases. A number of relevant observational studies (10% of all research studies) would have been missed, however, by excluding built environment and grey literature databases. In an area lacking in interventional research (housing/neighbourhoods and mental health) as many as 25% of all research studies would have been missed by ignoring the built environment and grey literature. Conclusions: When planning a systematic review of all types of evidence in a topic relating to the built environment and the health of the public, a range of bibliographical databases from various disciplines should be considered.

Microbial dehalogenation of trichloroacetic acid.

A pure bacterial culture and a two-membered mixed culture were isolated that degraded trichloroacetic acid if a second, readily metabolizable substrate was present in the growth medium. Previous doubts over the microbial dehalogenation of trichloroacetic acid (TCA) may be due to its inability to act as a sole carbon and energy source. TCA dehalogenation was associated with conventional 2-haloalkanoic acid dehalogenases but oxalate, the putative dehalogenase product, was not detected. CO2 was produced rapidly and concomitantly with Cl− ion release during dehalogenation of TCA. An alternative mechanism is suggested for TCA dehalogenation via an initial decarboxylation reaction. This mechanism predicts that carbon monoxide is a product of TCA decarboxylation and it was significant that one of the organisms isolated,Pseudomonas carboxydohydrogens, was a carboxytroph and a second was an unidentified facultative methylotroph.

The value and impact of information provided through library services for patient care: developing guidance for best practice

INTRODUCTION Previous impact tool-kits for UK health libraries required updating to reflect recent evidence and changes in library services. The National Knowledge Service funded development of updated guidance. METHODS Survey tools were developed based on previous impact studies and a systematic review. The resulting draft questionnaire survey was tested at four sites, and the interview schedule was investigated in a fifth area. A literature search in ASSIA, Google Scholar, INTUTE, LISA, LISTA, SCIRUS, Social Sciences Citation Index (Web of Knowledge), and the major UK University and National Libraries Catalogue (COPAC), identified ways to improve response rates. Other expert advice contributed to the guidance. RESULTS The resulting guidance contains evidence-based advice and a planning pathway for conducting an impact survey as a service audit. The survey tools (critical incident questionnaire and interview schedule) are available online. The evidence-based advice recommends personalizing the request, assuring confidentiality, and using follow-up reminders. Questionnaires should be brief, and small incentives, such as a lottery draw should be considered. Bias is minimized if the survey is conducted and analysed by independent researchers. CONCLUSION The guidance is a starting point for a pragmatic survey to assess the impact of health library services.

Systematic review of multi-symptom conditions in Gulf War veterans.

BACKGROUND Gulf War veterans have a number of health complaints. We therefore decided to carry out a systematic review to identify and summarize the findings from studies that have assessed multi-symptom conditions in Gulf War veterans and in an unexposed comparison group. METHOD Studies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they compared the prevalence of chronic fatigue syndrome, multiple chemical sensitivity, CDC-defined chronic multi-symptom illness, fibromyalgia, or symptoms of either fatigue or numbness and tingling in Gulf War veterans and non-Gulf veterans. A total of 2401 abstracts were independently reviewed by two authors. RESULTS Twenty-three publications fulfilled the inclusion criteria. Gulf deployment was most strongly associated with chronic fatigue syndrome (OR 3.8, 95% CI 2.2-6.7). Gulf War veterans were also approximately three and a half times more likely than non-Gulf veterans to report multiple chemical sensitivity or chronic multi-symptom illness as defined by CDC. The methodological quality of the studies varied but the later and larger studies were of a high methodological standard with robust sampling strategies, adequate response rates and good adjustment for confounders. CONCLUSIONS The results support the hypothesis that deployment to the Gulf War is associated with greater reporting of multi-symptom conditions.

Using bibliometrics to define the quality of primary care research

A useful international benchmark, but should not be used to allocate resources

Evidence synthesis, upstream determinants and health inequalities: the role of a proposed new Cochrane Public Health Review Group

Within public health decision making, there has been an increasing awareness of the need for better syntheses of evidence related to interventions addressing upstream, population-level determinants of health and health inequalities. This includes focusing greater attention on ways of integrating evidence from a range of sources and on best ways of using what evidence is currently available, while remaining aware of its limitations. 1 Inherent within this is the need to consider further the contribution and value of multiple forms of evidence to the evidence base rather than a stringent focus on ranking evidence by more traditional scientific measures. Whilst we would argue that well-conducted experimental studies provide strong evidence on intervention effectiveness it is not always possible to carry out such studies when evaluating complex public health interventions. Accordingly, exploring ways of incorporating diverse evidence sources into systematic reviews, together with a realistic view of the scope, strengths and limitations of such evidence, needs consideration if public health is to make an effective contribution to impacting health inequalities and the social determinants of health. High quality systematic reviews can inform both the development of further primary research as well as policymaking, which does not absolve the need for better primary research on the effectiveness and economic efficiency of interventions and policies with regards to health inequalities, 2 but primary research must be informed by better understanding of what research already exists and hence where the gaps are.

Systematic Review and Meta-Analysis of Randomised Trials to Ascertain Fatal Gastrointestinal Bleeding Events Attributable to Preventive Low-Dose Aspirin: No Evidence of Increased Risk

Background Aspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding. We therefore present a literature search and meta-analysis to ascertain fatal events attributable to low-dose aspirin. Methods In a systematic literature review we identified reports of randomised controlled trials of aspirin in which both total GI bleeding events and bleeds that led to death had been reported. Principal investigators of studies in which fatal events had not been adequately described were contacted via email and asked for further details. A meta-analyses was then performed to estimate the risk of fatal gastrointestinal bleeding attributable to low-dose aspirin. Results Eleven randomised trials were identified in the literature search. In these the relative risk (RR) of ‘major’ incident GI bleeding in subjects who had been randomised to low-dose aspirin was 1.55 (95% CI 1.33, 1.83), and the risk of a bleed attributable to aspirin being fatal was 0.45 (95% CI 0.25, 0.80). In all the subjects randomised to aspirin, compared with those randomised not to receive aspirin, there was no significant increase in the risk of a fatal bleed (RR 0.77; 95% CI 0.41, 1.43). Conclusions The majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.