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ObjectivesDuring a prospective study of S. aureus carriage in Royal Marines (RM) recruits, six S. argenteus strains were identified in four recruits undertaking military training together. As S. argenteus sepsis leads to mortality similar to S. aureus, we determined the potential for person-to-person transmission, to evaluate future outbreak risk.MethodsWe used whole-genome sequencing to characterise S. argenteus and investigate phylogenetic relationships between isolates. Participant colonisation with S. aureus and skin and soft tissue infection acquisition were recorded.ResultsAll six S. argenteus strains were spa-type t5078, ST2250. Strains were detected in 4/40 recruits in the same troop (training cohort) in weeks 1, 6 or 15 of training. No mec, tsst or LukPV genes were detected. We identified differences of 10-35 core SNPs between S. argenteus from different recruits. In two recruits, two S. argenteus strains were isolated; these could be distinguished by 3 and 15 core SNPs in each case. S. argenteus was not identified in any one of the other 21 participating troops (1,012 recruits).ConclusionsThe identification of S. argenteus within a single troop from the total recruit population supports a common source for transmission, supported by SNP analysis. The high number of SNPs between some isolates may indicate a common source of diverse isolates or a high level of S. argenteus mutation in carriage. S. argenteus ST2250 is a newly recognised lineage; a better understanding of the frequency of genetic changes during transmission and transition from asymptomatic carriage to disease is required.

Objectives: During a prospective study of S. aureus carriage in Royal Marines recruits, six S. argenteus strains were identified in four recruits. As S. argenteus sepsis leads to mortality similar to S. aureus, we determined the potential for within same troop transmission, to evaluate future outbreak risk. Methods: We used whole-genome sequencing to characterise S. argenteus and investigate phylogenetic relationships between isolates. Results: S. argenteus strains (t5078, ST2250) were detected in 4/40 recruits in the same troop (training cohort) in weeks 1, 6 or 15 of training. No mec, tsst or LukPV genes were detected. We identified differences of 1-17 core SNPs between S. argenteus from different recruits. In two recruits, two S. argenteus strains were isolated; these could be distinguished by 2 and 15 core SNPs. Conclusions: The identification of S. argenteus within a single troop from the total recruit population suggests a common source for transmission, though high number of SNPs were identified, both within-host and within-cluster. The high number of SNPs between some isolates may indicate a common source of diverse isolates or a high level of S. argenteus mutation in carriage. S. argenteus is newly recognised species; and understanding of the frequency of genetic changes during transmission and transition from asymptomatic carriage to disease is required.

The introduction presents an overview of critical debates in relation to mysticism and medieval aesthetics, before offering a short case study of medieval and modern representation of the mystery of the Incarnation intended to highlight the key themes and tension address over the volume as a whole. An examination of the 'Incarnation Initials' of Insular Gospel Books and Gerald of Wales's discussion of the Gospels of Kildare highlights the importance of craft, materiality and the transcendent to these medieval works of art. Padraic Colum's mid-twentieth-century poem responds to the Book of Kells with a meditation on the practice of its creator. Finally, the paradox of worldly art being able both to facilitate and to hinder access to the divine is addressed in relation to some Middle English lyrics.

This essay argues that the glosses in the late fourteenth- to early fifteenth-century Middle English work þe Myrrour of Symple Soules are more theologically coherent than has previously been posited. Focusing on the discussion of “usages” that they contain, as well as on the importance of freedom, a case is made for reading many of the annotations as advocating a Thomist/ Bonaventurean account of deification, that is, an account of deification in which the soul loves God through a created habitus that allows the Holy Spirit to work in it through participation without obliterating it. Although a more theologically conservative understanding of deification than usually posited of the original Mirouer, it is argued that the translator demonstrates concern that his readers understand what it means to be deified in union with God, and as such sets out to offer them more than a “rhetoric of ecstasy.”

Currently, little is known about the length of time required to rehabilitate patients from stress fractures and their return to preinjury level of physical activity. Previous studies have looked at the return to sport in athletes, in a general population, where rehabilitation is not as controlled as within a captive military population. In this study, a longitudinal prospective epidemiological database was assessed to determine the incidence of stress fractures and the time taken to rehabilitate recruits to preinjury stage of training. Findings demonstrated a background prevalence of 5% stress fractures in Royal Marine training; femoral and tibial stress fractures take 21.1 weeks to return to training with metatarsal stress fractures being the most common injury taking 12.2 weeks. Rehabilitation from stress fractures accounts for 814 weeks of recruit rehabilitation time per annum. Stress fracture incidence is still common in military training; despite this stress fracture recovery times remain constant and represent a significant interruption in training. It takes on average 5 weeks after exercise specific training has restarted to reenter training at a preinjury level, regardless of which bone has a stress fracture. Further research into their prevention, treatment, and rehabilitation is required to help reduce these burdens.

The objective was to assess the long-term survival (5-15 years) in 463 women, with stages IIb-IV epithelial carcinoma of the ovary and to compare their survival with that of a normal population matched for age and sex. Statistical analysis of 463 women, with stages IIb-IV epithelial cancer of the ovary, who were participants in two consecutive North Thames Ovary Group randomized trials, which took place between 1985 and 1994, was performed. The median follow-up period was 10.5 years. The women were treated with debulking surgery, where possible, and adjuvant platinum chemotherapy. One of the randomized groups in the first North Thames trial also received total abdominal radiotherapy. Survival rates at 5, 10, and 15 years were assessed. Prognostic factors for long-term survival were determined using a mathematical model to separate early effects from late effects. The ratio of observed to expected deaths compared to the normal population was calculated. Overall survival at 5 years was 21% (95% confidence intervals 17.5-25%), at 10 years was 13.5% (95% confidence intervals 10.5-17%), and at 15 years was 12% (95% confidence intervals 9-16%). The important prognostic factors for long-term survival were disease-free or minimal residual disease (a single remaining deposit2 cm) at initial surgery with tumor grade 1 and good performance status. Compared with the normal population (1995 data), the ratio of observed to expected deaths after start of chemotherapy at 5 years was 14.1 (P0.001 Fisher's exact test), at 9-10 years 4.9 (P = 0.0033, Fisher's exact test), while in the 11- to 15-year period it had dropped to 2.75 (P = 0.090, Fisher's exact test), which was not significantly different. Patients with advanced cancer of the ovary, who survive 11 years or longer, have a life expectancy which is very similar to that of a normal population of women of the same age. Women with advanced ovarian cancer have an improved chance of long-term survival following treatment if they present with minimal residual disease after primary surgical debulking, grade 1 tumors, and good performance status.

We evaluated the sequential use of carboplatin, paclitaxel and topotecan in patients with advanced, previously untreated ovarian cancer. In total, 43 patients with advanced ovarian cancer and >1 cm residual disease were treated with sequential carboplatin (area-under-the-curve (AUC) 5 days 1 and 22), paclitaxel (175 mg m(-2) days 43 and 64) and topotecan (1.5 mg m(-2) daily for 5 days from days 85, 106, 127 and 148). Median age of patients was 61 years. Median follow-up was 22.2 months (range 0.76-50.6 months). In all, 34 (79%) patients received all eight cycles of treatment and nine (21%) withdrew. Of the 29 evaluable patients, 19 (66%) responded according to WHO and 30 of 36 (83%) patients according to CA125. The best overall response (CA125 and/or WHO) was 77% (33 of 43 patients). The response rates to sequential drugs based on >50% fall in CA125 were as follows: carboplatin, 77% (30 of 39 patients); paclitaxel, 65% (15 of 23 patients); topotecan, 38% (five of 13 patients). Two patients responded to paclitaxel and one to topotecan after failure to respond to preceding chemotherapy. Median survival and time to progression was 22.24 and 10.61 months, respectively. This study demonstrates that sequential chemotherapy with just two initial courses of carboplatin is a reasonable way to introduce new agents into first-line therapy for poor prognostic ovarian cancer patients.

BACKGROUND: Response rates to chemotherapy in relapsed, platinum resistant epithelial ovarian cancer remain poor. We have explored the effectiveness of weekly cisplatin combined with prolonged oral etoposide in this patient group. PATIENTS AND METHODS: Forty-two women with relapsed, advanced ovarian cancer were treated with cisplatin 60 mg/m2 on days 1, 8, 15, 29, 36 and 43 and oral etoposide 50 mg given from day 1-14 and day 29-43. In those who were responding and tolerating treatment (n = 13) oral etoposide 50 mg was continued for two further cycles (days 1-21 repeated every 28 days). The interval since last platinum containing chemotherapy was > 6 months in 28 patients and < 6 months in 16 patients. RESULTS: Thirty-six patients were evaluable for response according to CA 125 criteria giving an overall response rate of 44%. The response rate in evaluable patients declined with increasing numbers of previous treatments: 57% with one prior treatment, 42% with two, 40% with three or more. The response rate in patients who had received platinum chemotherapy within six months prior to treatment was 46%. The only significant non-haematological toxicity was nausea and vomiting in 4 patients who experienced greater than grade 2 toxicity. The number of patients experiencing haematological toxicity more than grade 2 was as follows: haemoglobin 3, white blood count 12, platelets 6. Sixteen patients had dose delays and two had dose reductions. CONCLUSION: We conclude that this short but intensive regimen provides worthwhile response rates, even in those patients who would ordinarily be considered refractory to platinum, and has an acceptable toxicity profile.

An ultrasonic spray pyrolysis (USP) system has been used to deposit thick films of YBa/sub 2/Cu/sub 3/O/sub 7-x/ on [100] LaAlO/sub 3/. Nitrate precursors with a Y:Ba:Cu ratio of 1:2:0.6 have been used with a deposition temperature of 900/spl deg/C and annealing temperature of 500/spl deg/C. Growth rates as high as 1 /spl mu/m per minute have resulted in epitaxial growth of biaxially aligned ( 10/sup 4/ A.cm/sup -2/, 1 T, 77 K. It has been previously shown that lower nitrate precursor concentration, and hence decreased growth rate, has resulted in improved superconducting properties. The main objective of this paper is to investigated the effect of deposition temperature and post-annealing on the properties of the superconducting films.

Background: There is a need to delineate how the best available serum marker for ovarian cancer, CA 125 should be used in monitoring the treatment of individual patients, and in clinical trials. Patients and methods: The situations where measurement of CA 125 could alter the management of individual patients during therapy and at relapse were critically analysed. Precise definitions for response according to CA 125 were first developed and tested on 989 patients receiving first line therapy and have since been tested on over 2000 patients in phase 2 trials. Precise definitions for progression were developed from 71 patients during and on 255 patients both during and after initial chemotherapy. Results: In individual patient management, progression on initial chemotherapy can be demonstrated by serial rise in CA 125 suggesting the need for a change in therapy. A confirmed doubling of CA 125 from the upper limit of ormal during follow up accurately predicts relapse. This endpoint needs prospective testing for use in clinical trials. Precise definitions of response based on a 50% or 75% fall in CA 125 levels accurately predicts whether a cytotoxic agent is active against ovarian cancer. Conclusion: Precise definitions of response based on CA 125 should be used in phase 2 trials of new cytotoxic drugs.

Summary Background Background: In a previous phase I–II trial we showed that maximum tolerable dose (MTD) of 5-fluorouracil (5-FU) a weekly 48-hour continuous infusion (CI) was 3.5 g/m2. In a subsequent confirniative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained, and a median survival of 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. On this basis we attempted to modulate high-dose 5-FU (3 g/m2) with oral leucovorin (LV) but the regimen too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned. Patients and methods From July 1992 to June 1994, 110 previously untreated patients with advanced, measurable colorectal cancer were included in a multicenter study. The patients received, on an outpatient basis, 5-FU 2 g/m2 by continuous infusion for 48 hours once a week until progression or the appearance of toxic effects. Oral leucovorin (60 mg every six hours) was also given during the 5-FU infusion. Results Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9–2). Three complete responses and 36 partial responses were observed. The overall response rate was 37.5% (95% CI, 28% to 46.8%), the median time to progression 7.4 months and median survival 14.5 months. W.H.O. grade 3 diarrhea occurred in 27 patients (24.5%); grade 3 mucositis was observed in 9 (8.1%) patients and grade 4 in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients, while grade 3 hand-foot syndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurred in one patient and grade 3–4 thrombocytopenia in two. Conclusion Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as the main limiting toxic effects. Its antitumor activity does not seem superior to that obtained with a weekly 48-hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.

Summary Background: Many studies have shown that CA 125 levels frequently rise prior to clinical evidence of progression of ovarian cancer. For clinical trials an accepted definition of progression according to CA 125 is required. We therefore determined what change in CA 125 level was the most accurate predictor of relapse in patients on follow up after therapy for ovarian cancer. Patients and methods: Serial CA 125 levels were studied from 255 patients entering the North Thames Ovary Trial of 5 versus 8 courses of chemotherapy. An initial analysis was made 2 months after closure of the trial, a more detailed analysis was made after 81 confirmed relapses among evaluable patients and a final analysis was made one year later with longer follow-up. Results: On the basis of the results from the interim analyses and the cut-off level of 22-35 U/ml used by different laboratories, 30 U/ml was chosen as the upper limit of normal. In the final analysis a doubling of CA 125 from the upper limit of normal was defined as progression. Using this method sensitivity was 85.9%, specificity 91.3%, positive predictive value 94.8%, and negative predictive value was 77.8%. Insisting on a confirmatory elevated CA 125 level reduced the false positive rate to

A number of studies have suggested that serum CA 125 levels may be an important prognostic factor for survival of patients with ovarian carcinoma. We investigated, in a large group of patients from 11 UK centers, which combination of CA 125 measurements provided the best prognostic index, and whether the predictive power could be improved by the addition of other factors. Analysis of the data from 248 patients showed that the absolute value of the third CA 125 sample was the single most important factor for predicting progression at 12 months, with the addition of residual bulk only slightly improving the predictive power. Seventy-four patients had CA 125> 70, and of these 57% were correctly predicted to progress or die within 12 months, but 43% remained alive and progression free. The best predictor for progression produced a false positive rate of 19%. We therefore conclude that prognostic information based upon CA 125 measurements up to the start of the third course of initial chemotherapy is not accurate enough to be used to manage individual patients.

AIMS: The aim of this review was to assess whether restraint and seclusion are safe and effective interventions for the short-term management of disturbed/violent behaviour. Staff and service user perspectives on the use of these interventions were also considered. The review was undertaken as part of the development process for a national guideline on the short-term management of disturbed/violent behaviour in adult psychiatric inpatient settings and emergency departments in the United Kingdom. METHOD: An exhaustive literature search was undertaken. Systematic reviews, before and after studies, as well as qualitative studies were included. Searches were run from 1985 to 2002. FINDINGS: Thirty-six eligible studies were identified. However, none were randomised controlled trials. Most of the included studies had many limitations, such as small sample sizes, confounders not adequately accounted for, potential selection bias, poorly reported results, and lack of clarity as to whether mechanical restraints were used. This review must therefore be viewed as a mapping exercise, which illustrates the range and quality of studies that have been undertaken in this area to date. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Insufficient evidence is available to determine whether seclusion and restraint are safe and/or effective interventions for the short-term management of disturbed/violent behaviour in adult psychiatric inpatient settings. These interventions should therefore be used with caution and only as a last resort once other methods of calming a situation and/or service user have failed.

There is a need to delineate how the best available serum marker for ovarian cancer, CA 125 should be used in monitoring the treatment of individual patients, and in clinical trials.The situations where measurement of CA 125 could alter the management of individual patients during therapy and at relapse were critically analysed. Precise definitions for response according to CA 125 were first developed and tested on 989 patients receiving first line therapy and have since been tested on over 2000 patients in phase 2 trials. Precise definitions for progression were developed from 71 patients during and on 255 patients both during and after initial chemotherapy.In individual patient management, progression on initial chemotherapy can be demonstrated by serial rise in CA 125 suggesting the need for a change in therapy. A confirmed doubling of CA 125 from the upper limit of normal during follow up accurately predicts relapse. This endpoint needs prospective testing for use in clinical trials. Precise definitions of response based on a 50% or 75% fall in CA 125 levels accurately predicts whether a cytotoxic agent is active against ovarian cancer.Precise definitions of response based on CA 125 should be used in phase 2 trials of new cytotoxic drugs.

There is no clear data on the optimum number of courses of platinum chemotherapy required for treating advanced ovarian cancer. A prospective randomised trial was performed to compare five with eight courses of either carboplatin 400 mg/m2 or cisplatin 75 mg/m2 given four-weekly to patients with stage IC-IV ovarian cancer.225 patients were entered into the study and 233 were eligible for randomisation: 118 to five courses and 115 to eight courses. In each randomisation, half the patients received carboplatin and half received cisplatin.The mean number of courses received on the five arm was 4.74 and on the eight arm, 6.42, an increase of 35%. The median survival for all patients was 24 months with the median survival for the 156 patients with stage 3 disease being 21 months. No difference was detected in survival (P = 0.53) or time to progression from initial surgery (P = 0.29) between the two arms of the trial. False-negative calculations based on a multivariate analysis show that the trial currently has 95% power for excluding a difference of 10% in favour of the eight course arm at three years.There is insufficient evidence at the present time to justify more than five courses of first-line single agent platinum chemotherapy in the management of advanced ovarian cancer.

A palliative combination chemotherapy regimen (FaFEC) was developed for patients with relapsed epithelial ovarian cancer in particular patients relapsing after, or ineligible to enter, phase II trials, usually due to lack of evaluable disease. Forty-six patients were enrolled. Patients had received a mean of 2.3 previous drug regimens and nine (19%) had intestinal obstruction at the start of FaFEC. The majority of patients were inevaluable by WHO criteria so objective response data was obtained from serial serum CA125 evaluations. A serological response was demonstrated in 8/44 (18%). The responders included 6/27 women who had a prior relapse-free interval of less than 3 months, four who were resistant to platinum chemotherapy and three patients who had previously received paclitaxel. The major (WHO grade 3/4) toxicities included leucopenia (six patients), anemia (three patients), thrombocytopenia (two patients), nausea and vomiting (four patients) and severe infections (five patients). Following FaFEC the median time to failure was 0.48 years and the median survival was 0.66 years. FaFEC was effective in this group of very poor prognosis patients. The serological response rate of 18% is noteworthy considering the multiple prior treatments that patients had received and the short treatment free intervals. FaFEC may be useful second line therapy in epithelial ovarian cancer patients ineligible for phase II studies and should be considered for a randomized comparison with paclitaxel.

Twenty-two asymptomatic women with rising CA 125 levels after chemotherapy for ovarian cancer were entered into a trial of isotretinoin combined with calcitriol. Tumours were evaluated according to precise criteria based on serial CA 125 levels and by comparing regression slopes of CA 125 before and during therapy. There was no evidence based on CA 125 of any responses or significant change in tumour growth rate.

Background: Rapid tranquillisation is used when control of agitation, aggression or excitement is required. Throughout the UK there is no consensus over the choice of drugs to be used as first line treatment. The NICE guideline on the management of violent behaviour involving psychiatric inpatients conducted a systematic examination of the literature relating to the effectiveness and safety of rapid tranquillisation (NICE, 2005). This paper presents the key findings from that review and key guideline recommendations generated, and discusses the implications for practice of more recent research and information.\ud \ud Aims: To examine the evidence on the efficacy and safety of medications used for rapid tranquillisation in inpatient psychiatric settings.\ud \ud Method: Systematic review of current guidelines and phase III randomised, controlled trials of medication used for rapid tranquillisation. Formal consensus methods were used to generate clinically relevant recommendations to support safe and effective prescribing of rapid tranquillisation in the development of a NICE guideline.\ud \ud Findings: There is a lack of high quality clinical trial evidence in the UK and therefore a ‘gold standard’ medication regime for rapid tranquillisation has not been established.\ud \ud Rapid tranquillisation and clinical practice: The NICE guideline produced 35 recommendations on rapid tranquillisation practice for the UK, with the primary aim of calming the service user to enable the use of psychosocial techniques.\ud \ud Conclusions and implications for clinical practice: Further UK specific research is urgently needed that provides the clinician with a hierarchy of options for the clinical practice of rapid tranquillisation.

Rabbits were immunised against casein and whey proteins from rat milk. The immune globulins were conjugated to fluorescein isothiocyanate and the labelled antibodies were used to stain histological sections. Casein was located in unfixed and fixed cryostat sections of lactating rat mammary glands but better preparations were obtained using fixed paraffin embedded material. Casein was consistently present in sections of lactating mammary glands and was found on the gastric mucosa of suckling baby rats; it was not, however, found in any other organ in the body. The localisation of whey proteins was unsatisfactory in cryostat sections and the antigenicity of these proteins was completely destroyed by histological fixation and paraffin embedding.

In an in vitro system containing no neutralizing antibody, `immune' macrophages remove T1 phage from the system more rapidly than do `non-immune' macrophages. The clearance of T1 phage from the in vitro system occurs in two phases, similar to those occurring in vivo. The results of the in vitro studies thus mirror the results of the in vivo studies previously described.

The clearance of a secondary dose of T1 bacteriophage from the circulation of the goldfish, lamprey and shore crab has been shown to be more rapid than the clearance of a primary dose of phage. The phenomenon occurs in the absence of any detectable humoral antibody and appears similar to that previously described in rabbits.