Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Design and evaluation of meningococcal vaccines through structure-based modification of host and pathogen molecules.

Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps

P-glycoprotein and breast cancer resistance protein in acute myeloid leukaemia cells treated with the Aurora-B Kinase Inhibitor barasertib-hQPA

<p>Abstract</p> <p>Background</p> <p>Aurora kinases play an essential role in orchestrating chromosome alignment, segregation and cytokinesis during mitotic progression, with both aurora-A and B frequently over-expressed in a variety of human malignancies. Over-expression of the ABC drug transporter proteins P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP) is a major obstacle for chemotherapy in many tumour types with Pgp conferring particularly poor prognosis in acute myeloid leukaemia (AML). Barasertib-hQPA is a highly selective inhibitor of aurora-B kinase that has shown tumouricidal activity against a range tumour cell lines including those of leukaemic AML origin.</p> <p>Methods</p> <p>Effect of barasertib-hQPA on the pHH3 biomarker and cell viability was measured in a panel of leukaemic cell lines and 37 primary AML samples by flow cytometry. Pgp status was determined by flow cytometry and BCRP status by flow cytometry and real-time PCR.</p> <p>Results</p> <p>In this study we report the creation of the cell line OCI-AML3DNR, which over-expresses Pgp but not BCRP or multidrug resistance-associated protein (MRP), through prolonged treatment of OCI-AML3 cells with daunorubicin. We demonstrate that Pgp (OCI-AML3DNR and KG-1a) and BCRP (OCI-AML6.2) expressing AML cell lines are less sensitive to barasertib-hQPA induced pHH3 inhibition and subsequent loss of viability compared to transporter negative cell lines. We also show that barasertib-hQPA resistance in these cell lines can be reversed using known Pgp and BCRP inhibitors. We report that barasertib-hQPA is not an inhibitor of Pgp or BCRP, but by using ¹⁴[C]-barasertib-hQPA that it is effluxed by these transporters. Using phosphoHistone H3 (pHH3) as a biomarker of barasertib-hQPA responsiveness in primary AML blasts we determined that Pgp and BCRP positive primary samples were less sensitive to barasertib-hQPA induced pHH3 inhibition (p = <0.001) than samples without these transporters. However, we demonstrate that IC₅₀inhibition of pHH3 by barasertib-hQPA was achieved in 94.6% of these samples after 1 hour drug treatment, in contrast to the resistance of the cell lines.</p> <p>Conclusion</p> <p>We conclude that Pgp and BCRP status and pHH3 down-regulation in patients treated with barasertib should be monitored in order to establish whether transporter-mediated efflux is sufficient to adversely impact on the efficacy of the agent.</p

Raising the profile of public health in an acute trust: collaborative working and changing perceptions.

A population health approach has not traditionally featured in the work of acute hospitals. Chelsea and Westminster NHS Foundation Trust (CWFT) is working to challenge perceptions and demonstrate the opportunity acute trusts have to lead the way in population health. Evidence suggests that CWFT's seven local clinical commissioning groups have 10% more emergency-specific 30-day readmissions than national rates. National data demonstrates alcohol-related attendances increases up to 70% of all weekend attendances. CWFT established an Alcohol Collaboration group to proactively address this alcohol burden. Led by a public health consultant, the group consists of seven local authorities, commissioners, third sector organisations, clinicians and a patient representative. The group engages monthly to support and direct the strategic development of hospital alcohol services. A trust audit suggested that 33% of our population consume alcohol at risky levels, 3% higher than national data, with 2% considered dependant. These findings have been used to engage and prompt discussions with clinical and non-clinical staff and feature as part of a trust-wide alcohol education programme targeting all frontline staff. Our staff and community partners increasingly recognise the opportunity in addressing health at a population level. The most significant achievement to date has been the launch of a 7-day alcohol support service without investment of additional resource. The groups collaborative approach is actively impacting perceptions at an acute trust and ultimately improving patient outcomes at a population level

Soil-transmitted Helminth infection in the Tiko Health District, South West Region of Cameroon: a post-intervention survey on prevalence and intensity of infection among primary school children

Introduction: Soil-transmitted helminths (STH) infection remains a public health problem in sub-Saharan Africa with children being most vulnerable. STH infection may result in impairment, permanent disability or death. Annual mass deworming has been implemented in the Tiko Health District (THD), however, no study has assessed the current prevalence of STH infection. This study aimed to determine the prevalence, intensity of STH infections and associated risk factors among school children. Methods: Two months after the school deworming exercise, 400 children were sampled from 10 schools in THD. Stool samples were collected and analyzed using the Kato-katz technique. Data on sociodemographic and behavioral factors were collected using questionnaires. Data were analyzed using SPSS and intensity of infection categorized following WHO recommendations. Descriptive data were calculated with frequencies (n) and proportions (%), prevalence and 95% confidence interval calculated for gender and age respectively. Differences in prevalence for socio-demographic characteristics and behavioral variables were calculated with Chi square (chi(2)). Independent sample t-test was used to compare the means in the number of eggs in feces between male and female school children. Results: The prevalence of STH was 1% (95% CI: 0.02-1.98). Ascaris lumbricoides was the only STH species detected and all cases were of low intensities. The arithmetic mean egg intensity was 3.1egg per gram of faeces. Rates of infection were similar between gender and age. Site of defecation showed an association with STH infection (chi(2)= 13.63, p= 0.03). Conclusion: These findings suggested a low prevalence of STH infection which could be explained by the prior deworming of children, modification in environmental and behavioral factors. Questions on effectiveness of annual mass deworming in achieving STH elimination targets need to be investigated further