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Anthony M.,University of Oxford | Bedford-Russell A.,Neonatal Unit | Cooper T.,Queen Marys Hospital Sidcup | Fry C.,Wellington House | And 7 more authors.
Archives of Disease in Childhood: Fetal and Neonatal Edition | Year: 2013

De novo guidance on the management of Gram-negative bacteria outbreaks in UK neonatal units was developed in 2012 by a Department of Health, England Antimicrobial Resistance and Healthcare Associated Infection working group. The recommendations included activation of an organisational response and establishing a control team when an outbreak is suspected; screening for the specific organism only during an outbreak; undertaking multidisciplinary reviews of cleaning routines, hand hygiene and Gram-negative bacteria transmission risks; considering deep-cleaning; cohorting colonised and infected babies preferably but not necessarily in isolation cubicles; and considering reducing beds or closing a unit to new admissions as a way of improving spacing and staff:patient ratios until the outbreak is under control. The group advised establishing mechanisms to communicate effectively across the network; informing parents of the outbreak as early as possible, and providing prewritten 'infection outbreak' information sheets. For prevention of outbreaks, the group advised meeting national staffing and cot-spacing requirements; following a Water Action Plan; using infection reduction care bundles and benchmarking; and introducing breast milk early and limiting antibiotic use.

Smith A.M.,University College London | Sewell G.W.,University College London | Levine A.P.,University College London | Chew T.S.,University College London | And 7 more authors.
Immunology | Year: 2015

Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD. © 2014 The Authors. Immunology published by John Wiley & Sons Ltd.

Payne H.,UCLH NHS Foundation Trust | Cornford P.,University of Liverpool
Urologic Oncology: Seminars and Original Investigations | Year: 2011

Prostate specific antigen (PSA) was introduced as a prostate cancer screening tool more than 20 years ago. However, there is continuing debate regarding its utility in screening for prostate cancer. Mass screening is costly, may result in the diagnosis and treatment of prostate cancers that never become clinically significant, and the evidence of a subsequent reduction in mortality is inconclusive. In addition to its role in screening, PSA is also used to monitor the progression of the disease, both localized and metastatic. Although the evidence is contradictory, PSA is still an important tool for monitoring patient progression following treatment of definitive localized prostate cancer. However, its use in monitoring castrate-resistant prostate cancer (CRPC) is more controversial, particularly in the context of novel targeted treatments, which may have little impact on PSA levels. These issues highlight the urgent need to identify prostate cancer biomarkers that will improve early disease detection, increase accuracy of diagnosis, determine the aggressiveness of disease, and monitor treatment efficacy, particularly in late-stage disease. This review discusses the key issues associated with the use of PSA as an early screening tool for prostate cancer, as a prognostic marker to measure disease progression in both early- and late-stage prostate cancer, and as a surrogate endpoint in clinical trials with new agents. © 2011 Elsevier Inc.

OBJECTIVES To report the final analysis of a Phase II trial, which investigated the safety and efficacy of the specific endothelin A receptor antagonist zibotentan (AstraZeneca, Macclesfield, UK) in patients with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS Patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain were randomized to receive once-daily oral tablets of zibotentan 10 mg, 15 mg or placebo. The primary endpoint was the time to progression and secondary endpoints included overall survival, change in the number of bone metastases, and safety. RESULTS In total, 312 patients were randomized (placebo, n = 107; zibotentan 10 mg, n = 107; zibotentan 15 mg, n = 98). The median duration of study treatment and median follow-up time were 4 and 22 months, respectively. At the final analysis, there were no statistical differences of the primary outcome of time to progression between treatment groups, although an improvement in overall survival was observed in the zibotentan groups compared to placebo. Consistent with the previous analyses for overall survival, hazard ratios (HRs) of less than one were sustained for both zibotentan 15 mg (HR, 0.76; 80% CI, 0.61-0.94; P = 0.103) and 10 mg (HR, 0.83; 80% CI, 0.67-1.02; P = 0.254). The most commonly reported adverse events considered to be related to zibotentan treatment were peripheral oedema, headache and nasal congestion. CONCLUSIONS The results obtained in the present study support endothelin A receptor antagonism as an approach for treating patients with CRPC. To confirm the survival signal observed in the present study, zibotentan is being investigated further in the ENdoTHelin A USE (ENTHUSE) Phase III clinical trial programme. © 2010 DRUG SAFETY RESEARCH UNIT.

Payne H.,UCLH NHS Foundation Trust | Pearcy R.,Plymouth Hospitals
Journal of Men's Health | Year: 2012

Castration-resistant prostate cancer (CRPC) is associated with multiple symptoms that have a significant impact on patients' health-related quality of life (HRQoL). We were interested to establish the extent to which disease and treatment-related symptoms affect the HRQoL of patients with CRPC from the patients' perspective, so we undertook a review of current literature and also obtained feedback at an international meeting. Our review of evidence from the literature found that the majority of patients with CRPC are significantly affected by a number of disease- and treatment-related symptoms that have a negative impact on their HRQoL. These findings highlighted the need for treatment decisions to be based on an assessment of quality as well as quantity of life for this patient population. We also established that there are substantial differences in the perception of HRQoL between patients and their physicians. Physicians remain the most direct influence on patient choice, therefore they have a responsibility to fully inform patients about their disease stage, the available treatment options and potential impact on HRQoL. Despite advances in the treatment and management of CRPC, further improvements in HRQoL are necessary. As a consequence, all future treatment approaches for CRPC should take into account both survival benefit and the impact on HRQoL. Furthermore, patients, their partners and physicians should all be involved in the treatment decision-making process. This should include an assessment of HRQoL to ensure potential impact and benefit is fully understood. © 2011 WPMH GmbH.

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