Bacteriophage T5 gene D10 encodes a branch-migration protein

Helicases catalyze the unwinding of double-stranded nucleic acids where structure and phosphate backbone contacts, rather than nucleobase sequence, usually determines substrate specificity. We have expressed and purified a putative helicase encoded by the D10 gene of bacteriophage T5. Here we report that this hitherto uncharacterized protein possesses branch migration and DNA unwinding activity. The initiation of substrate unwinding showed some sequence dependency, while DNA binding and DNA-dependent ATPase activity did not. DNA footprinting and purine-base interference assays demonstrated that D10 engages these substrates with a defined polarity that may be established by protein-nucleobase contacts. Bioinformatic analysis of the nucleotide databases revealed genes predicted to encode proteins related to D10 in archaebacteria, bacteriophages and in viruses known to infect a range of eukaryotic organisms

Evidence for a persistent, major excess in all cause admissions to hospital in children with type-1 diabetes: results from a large Welsh national matched community cohort study

OBJECTIVES: To estimate the excess in admissions associated with type1 diabetes in childhood. DESIGN: Matched-cohort study using anonymously linked hospital admission data. SETTING: Brecon Group Register of new cases of childhood diabetes in Wales linked to hospital admissions data within the Secure Anonymised Information Linkage Databank. POPULATION: 1577 Welsh children (aged between 0 and 15 years) from the Brecon Group Register with newly-diagnosed type-1 diabetes between 1999–2009 and 7800 population controls matched on age, sex, county, and deprivation, randomly selected from the local population. MAIN OUTCOME MEASURES: Difference in all-cause hospital admission rates, 30-days post-diagnosis until 31 May 2012, between participants and controls. RESULTS: Children with type-1 diabetes were followed up for a total of 12 102 person years and were at 480% (incidence rate ratios, IRR 5.789, (95% CI 5.34 to 6.723), p<0.0001) increased risk of hospital admission in comparison to matched controls. The highest absolute excess of admission was in the age group of 0–5 years, with a 15.4% (IRR 0.846, (95% CI 0.744 to 0.965), p=0.0061) reduction in hospital admissions for every 5-year increase in age at diagnosis. A trend of increasing admission rates in lower socioeconomic status groups was also observed, but there was no evidence of a differential rate of admissions between men and women when adjusted for background risk. Those receiving outpatient care at large centres had a 16.1% (IRR 0.839, (95% CI 0.709 to 0.990), p=0.0189) reduction in hospital admissions compared with those treated at small centres. CONCLUSIONS: There is a large excess of hospital admissions in paediatric patients with type-1 diabetes. Rates are highest in the youngest children with low socioeconomic status. Factors influencing higher admission rates in smaller centres (eg, “out of hours resources”) need to be explored with the aim of targeting modifiable influences on admission rates

A comparison of comorbidity measures for predicting mortality after elective hip and knee replacement : a cohort study of data from the National Joint Registry in England and Wales

Background The risk of mortality following elective total hip (THR) and knee replacements (KR) may be influenced by patients’ pre-existing comorbidities. There are a variety of scores derived from individual comorbidities that can be used in an attempt to quantify this. The aims of this study were to a) identify which comorbidity score best predicts risk of mortality within 90 days or b) determine which comorbidity score best predicts risk of mortality at other relevant timepoints (30, 45, 120 and 365 days). Patients and methods We linked data from the National Joint Registry (NJR) on primary elective hip and knee replacements performed between 2011–2015 with pre-existing conditions recorded in the Hospital Episodes Statistics. We derived comorbidity scores (Charlson Comorbidity Index—CCI, Elixhauser, Hospital Frailty Risk Score—HFRS). We used binary logistic regression models of all-cause mortality within 90-days and within 30, 45, 120 and 365-days of the primary operation using, adjusted for age and gender. We compared the performance of these models in predicting all-cause mortality using the area under the Receiver-operator characteristics curve (AUROC) and the Index of Prediction Accuracy (IPA). Results We included 276,594 elective primary THRs and 338,287 elective primary KRs for any indication. Mortality within 90-days was 0.34% (N = 939) after THR and 0.26% (N = 865) after KR. The AUROC for the CCI and Elixhauser scores in models of mortality ranged from 0.78–0.81 after THR and KR, which slightly outperformed models with ASA grade (AUROC = 0.77–0.78). HFRS performed similarly to ASA grade (AUROC = 0.76–0.78). The inclusion of comorbidities prior to the primary operation offers no improvement beyond models with comorbidities at the time of the primary. The discriminative ability of all prediction models was best for mortality within 30 days and worst for mortality within 365 days. Conclusions Comorbidity scores add little improvement beyond simpler models with age, gender and ASA grade for predicting mortality within one year after elective hip or knee replacement. The additional patient-specific information required to construct comorbidity scores must be balanced against their prediction gain when considering their utility

Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity

The coevolution of humans and infectious agents has exerted selective pressure on the immune system to control potentially lethal infections. Correspondingly, pathogens have evolved with various strategies to modulate and circumvent the host's innate and adaptive immune response. Schistosoma species are helminth parasites with genes that have been selected to modulate the host to tolerate chronic worm infections, often for decades, without overt morbidity. The modulation of immunity by schistosomes has been shown to prevent a range of immune-mediated diseases, including allergies and autoimmunity. Individual immune-modulating schistosome molecules have, therefore, therapeutic potential as selective manipulators of the immune system to prevent unrelated diseases. Here we show that S. mansoni eggs secrete a protein into host tissues that binds certain chemokines and inhibits their interaction with host chemokine receptors and their biological activity. The purified recombinant S. mansoni chemokine binding protein (smCKBP) suppressed inflammation in several disease models. smCKBP is unrelated to host proteins and is the first described chemokine binding protein encoded by a pathogenic human parasite and may have potential as an antiinflammatory agent

A quantitative release assessment for the noncommercial movement of companion animals : risk of rabies reintroduction to the United Kingdom

In 2004, the European Union (EU) implemented a pet movement policy (referred to here as the EUPMP) under EU regulation 998/2003. The United Kingdom (UK) was granted a temporary derogation from the policy until December 2011 and instead has in place its own Pet Movement Policy (Pet Travel Scheme (PETS)). A quantitative risk assessment (QRA) was developed to estimate the risk of rabies introduction to the UK under both schemes to quantify any change in the risk of rabies introduction should the UK harmonize with the EU policy. Assuming 100 % compliance with the regulations, moving to the EUPMP was predicted to increase the annual risk of rabies introduction to the UK by approximately 60-fold, from 7.79 × 10(-5) (5.90 × 10(-5) , 1.06 × 10(-4) ) under the current scheme to 4.79 × 10(-3) (4.05 × 10(-3) , 5.65 × 10(-3) ) under the EUPMP. This corresponds to a decrease from 13,272 (9,408, 16,940) to 211 (177, 247) years between rabies introductions. The risks associated with both the schemes were predicted to increase when less than 100 % compliance was assumed, with the current scheme of PETS and quarantine being shown to be particularly sensitive to noncompliance. The results of this risk assessment, along with other evidence, formed a scientific evidence base to inform policy decision with respect to companion animal movement

Timing of Radiotherapy (RT) after Radical Prostatectomy (RP): Long-term outcomes in the RADICALS-RT trial [NCT00541047]

Background The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for PSA failure. Methods RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, pre-op PSA≥10ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT (“Adjuvant-RT”) or an observation policy with salvage RT for PSA failure (“Salvage-RT”) defined as PSA≥0.1ng/ml or 3 consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5Gy/20 fractions or 66Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant metastasis, designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10yr with Adjuvant-RT. Secondary outcome measures were bPFS, freedom-from-non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; HR<1 favours Adjuvant-RT. Findings Between Oct-2007 and Dec-2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with median age 65yr. 93% (649/697) Adjuvant-RT reported RT within 6m after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10yr FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 (95%CI 0·43–1·07, p=0·095). Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95%CI 0.667–1.440, p=0.917). Adjuvant-RT reported worse urinary and faecal incontinence one year after randomisation (p=0.001); faecal incontinence remained significant after ten years (p=0.017). Interpretation Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy

On the role of d-d electron correlations in the cohesion and ferromagnetism of transition metals

The role of d-d correlations in the stability of phases in transition metals is studied in a semi-quantitative way, using a second-order perturbation formula which can be related to Gutzwiller's approximation. This deviation from the Hartree-Fock approximation increases the cohesion and decreases the surface tension; it destabilizes ferromagnetism, especially for nearly-half-full d bands. The maximum effect on cohesion and surface tension occurs for a half-filled d band; it remains small, at least for the 4d and 5d series.Le rôle des corrélations d-d dans la stabilité des phases des métaux de transition est étudié d'une façon semi-quantitative, en utilisant une formule de perturbation du second ordre qui peut être reliée à l'approximation de Gutzwiller. Cette déviation par rapport à Fapproximation de Hartree-Fock augmente la cohésion et réduit la tension superficielle; elle déstabilise le ferromagnétisme, particulièrement pour des bandes d presque à moitié pleines. L'effet maximum sur la cohésion et la tension superficielle se produit pour une bande d à moitié pleine; il reste petit, au moins pour les séries 4d et 5d