Mechanistically informed predictions of binding modes for carbocation intermediates of a sesquiterpene synthase reaction.

Sesquiterpenoids comprise a class of terpenoid natural products with thousands of compounds that are highly diverse in structure, generally containing a polycyclic carbon backbone that is constructed by a sesquiterpene synthase. Decades of experimental and computational studies have demonstrated that these enzymes generate a carbocation in the active site, which undergoes a series of structural rearrangements until a product is formed via deprotonation or nucleophile attack. However, for the vast majority of these enzymes the productive binding orientation of the intermediate carbocations has remained unclear. In this work, a method that combines quantum mechanics and computational docking is used to generate an all-atom model of every putative intermediate formed in the context of the enzyme active site for tobacco epi-aristolochene synthase (TEAS). This method identifies a single pathway that links the first intermediate to the last, enabling us to propose the first high-resolution model for the reaction intermediates in the active site of TEAS, and providing testable predictions

Incidence of Guillain-Barre syndrome among patients with Campylobacter infection: A general practice research database study

The association between Campylobacter infection and subsequent Guillain-Barre syndrome (GBS) has been well documented. To date, however, there exists no direct estimate of the incidence of GBS among patients with Campylobacter infection. Using the General Practice Research Database, we estimate the incidence of GBS in a cohort of patients presenting with Campylobacter enteritis to be 1.17/1000 person-years, a rate 77 times greater than that in the general population. The probability that an individual who develops Campylobacter enteritis will also develop GBS during the subsequent 2-month period is < 2/10,000

A meta-synthesis of qualitative studies of the link between anxiety, depression and perfectionism: Implications for treatment

Background: Meta-analyses show an association between perfectionism and depression and anxiety (negative affect), and that therapy for perfectionism impacts positively on negative affect. No systematic reviews have focused on qualitative studies of perfectionism. Aims: Our aim was to perform a systematic, meta-synthesis of qualitative literature to (i) help inform our understanding of how perfectionism is associated with negative affect, so that we can (ii) inform future development of treatment for perfectionism in young people and to make it more effective. Method: Included in the meta-synthesis were 37 qualitative studies. Results: Six themes related to perfectionism were found: (1) the association with negative affect, (2) self-worth dependent on achievement, (3) cognitive and behavioural maintaining factors, (4) the expectations of others, (5) effective elements of interventions, and (6) barriers to treatment. Conclusions: The qualitative literature supports the notion of perfectionism as an important construct to consider in reducing negative affect. While cognitive behavioural therapy for perfectionism holds promise as a treatment to target negative affect, there was a paucity of qualitative research, particularly related to young people. A greater understanding of the views of young people are required to help tailor more effective interventions for perfectionism that can impact negative affect in this group

Variation at the capsule locus, cps, of mistyped and non-typable Streptococcus pneumoniae isolates

The capsule polysaccharide locus (cps) is the site of the capsule biosynthesis gene cluster in encapsulated Streptococcus pneumoniae. A set of pneumococcal samples and non-pneumococcal streptococci from Denmark, the Gambia, the Netherlands, Thailand, the UK and the USA were sequenced at the cps locus to elucidate serologically mistyped or non-typable isolates. We identified a novel serotype 33B/33C mosaic capsule cluster and previously unseen serotype 22F capsule genes, disrupted and deleted cps clusters, the presence of aliB and nspA genes that are unrelated to capsule production, and similar genes in the non-pneumococcal samples. These data provide greater understanding of diversity at a locus which is crucial to the antigenic diversity of the pathogen and current vaccine strategies

Exposures associated with infection with Cryptosporidium in industrialised countries: a systematic review protocol

BackgroundCryptosporidium is a protozoan parasite of humans and other animals worldwide and is one of the greatest contributors to human diarrhoeal illness. Transmission can occur indirectly via contaminated food or water, or directly via contact with animals or other infected people. Risk exposures are often identified from outbreak investigations, but a subset of cases remains unexplained, and sources for sporadic disease and pathways to infection are still unclear.Given the few systematic syntheses of reported evidence in industrialised populations, the aim of this review is to consolidate the literature to describe exposures associated with human cryptosporidiosis in industrialised countries, specifically including the UK, and describe any differences between outbreak-associated and sporadic disease.Methods/designWhere relevant, methods will follow the recommendations made in the Cochrane Handbook for Systematic Reviews of Interventions. Three steps will be used to identify the literature including electronic database searching using PubMed, Scopus, Embase and Web of Science; reference list trawling; and an exploration of the grey literature. Screening of results will be undertaken by two reviewers using pre-defined criteria. Studies conducted in industrialised countries and reporting on human subjects will be included. All observational studies will be included where they report exposures and relevant quantitative results.Data will be extracted using a standardised form. Study quality will be assessed using the ROBINS-I tool. Data will be summarised presenting the papers’ main findings including population under study, outcomes, and exposures, and whether these were considered outbreak or sporadic cases. A narrative summary will also be included. Where populations are appropriate, available data will be pooled in a meta-analysis combining the significant exposures across studies.DiscussionThis review aims to consolidate the evidence for transmission routes and exposures for Cryptosporidium in industrialised countries, with particular reference to how these may apply to the UK. In addition, the review will seek to describe differences between outbreak and sporadic cases. This will help to identify those most vulnerable, highlighting pathways where interventions and public health response may be appropriate.Systematic review registrationPROSPERO number CRD42017056589.Electronic supplementary materialThe online version of this article (10.1186/s13643-018-0731-8) contains supplementary material, which is available to authorized users

A realist synthesis of websites containing content on perfectionism: Are the descriptions and advice empirically supported?

BACKGROUND: Perfectionism is a risk factor for depression and anxiety and is increasing in young people. It is important to understand the information that youth are exposed to about perfectionism on the internet and what may be required to make this more helpful in terms of accessing empirically supported descriptions and advice. METHODS: This research used novel methodology to investigate content about perfectionism on websites by conducting a realist synthesis of the definitions of perfectionism, and the degree to which websites contain empirically supported strategies and recognise the advantages and disadvantages of perfectionism. The results were presented to people aged 18 to 24 (N = 18) with a lived experience of anxiety/depression for feedback. RESULTS: The search yielded 992 websites, 266 of which were included in the synthesis; only one met the criteria for excellent quality with most (56%) judged as moderate. The feelings, thoughts, and behaviours that accompany perfectionism were commonly described, and strategies included identifying cognitions and developing alternatives, moving from self-criticism to self-compassion, normalising mistakes, adjusting goals, receiving practical support, and strategies for procrastination. The young people wanted further emphasis on depression and anxiety as consequences of perfectionism that contributed to a vicious cycle. They identified interventions were difficult, with greater levels of support needed. CONCLUSIONS: While most websites contained empirically supported information, the quality needs to improve, and further information needs to be provided on the links with anxiety and depression. Interventions for perfectionism need to have more focus on helping young people develop support networks

Farm management factors associated with bulk tank total bacterial count in Irish dairy herds during 2006/07

Research has shown that total bacterial count (TBC), which is the bacterial growth per ml of milk over a fixed period of time, can be decreased by good hygiene and farm management practices. The objective of the current study was to quantify the associations between herd management factors and bulk tank TBC in Irish spring calving, grass-based dairy herds. The relationship between bulk tank TBC and farm management and infrastructure was examined using data from 400 randomly selected Irish dairy farms where the basal diet was grazed grass. Herd management factors associated with bulk tank TBC were identified using linear models with herd annual total bacterial score (i.e., arithmetic mean of the natural logarithm of bulk tank TBC) included as the dependent variable. All herd management factors were individually analysed in a separate regression model, that included an adjustment for geographical location of the farm. A multiple stepwise regression model was subsequently developed. Median bulk tank TBC for the sample herds was 18,483 cells/ml ranging from 10,441 to 130,458 cells/ml. Results from the multivariate analysis indicated that the following management practices were associated with low TBC; use of heated water in the milking parlour; participation in a milk recording scheme; and tail clipping of cows at a frequency greater than once per year. Increased level of hygiene of the parlour and cubicles were also associated with lower TBC. Herd management factors associated with bulk tank TBC in Irish grazing herds were generally in agreement with most previous studies from confinement systems of milk production

Estimating the incidence of acute infectious intestinal disease in the community in the UK:A retrospective telephone survey

Objectives: To estimate the burden of intestinal infectious disease (IID) in the UK and determine whether disease burden estimations using a retrospective study design differ from those using a prospective study design. Design/Setting: A retrospective telephone survey undertaken in each of the four countries comprising the United Kingdom. Participants were randomly asked about illness either in the past 7 or 28 days. Participants: 14,813 individuals for all of whom we had a legible recording of their agreement to participate Outcomes: Self-reported IID, defined as loose stools or clinically significant vomiting lasting less than two weeks, in the absence of a known non-infectious cause. Results: The rate of self-reported IID varied substantially depending on whether asked for illness in the previous 7 or 28 days. After standardising for age and sex, and adjusting for the number of interviews completed each month and the relative size of each UK country, the estimated rate of IID in the 7-day recall group was 1,530 cases per 1,000 person-years (95% CI: 1135 – 2113), while in the 28-day recall group it was 533 cases per 1,000 person-years (95% CI: 377 – 778). There was no significant variation in rates between the four countries. Rates in this study were also higher than in a related prospective study undertaken at the same time. Conclusions: The estimated burden of disease from IID varied dramatically depending on study design. Retrospective studies of IID give higher estimates of disease burden than prospective studies. Of retrospective studies longer recall periods give lower estimated rates than studies with short recall periods. Caution needs to be exercised when comparing studies of self-reported IID as small changes in study design or case definition can markedly affect estimated rates

Socioeconomic status and infectious intestinal disease in the community: a longitudinal study (IID2 study).

Infectious intestinal diseases (IID) are common, affecting around 25% of people in UK each year at an estimated annual cost to the economy, individuals and the NHS of £1.5 billion. While there is evidence of higher IID hospital admissions in more disadvantaged groups, the association between socioeconomic status (SES) and risk of IID remains unclear. This study aims to investigate the relationship between SES and IID in a large community cohort.Longitudinal analysis of a prospective community cohort in the UK following 6836 participants of all ages was undertaken. Hazard ratios for IID by SES were estimated using Cox proportional hazard, adjusting for follow-up time and potential confounding factors.In the fully adjusted analysis, hazard ratio of IID was significantly lower among routine/manual occupations compared with managerial/professional occupations (HR 0.74, 95% CI 0.61-0.90).In this large community cohort, lower SES was associated with lower IID risk. This may be partially explained by the low response rate which varied by SES. However, it may be related to differences in exposure or recognition of IID symptoms by SES. Higher hospital admissions associated with lower SES observed in some studies could relate to more severe consequences, rather than increased infection risk