A randomised trial evaluating Bevacizumab as adjuvant therapy following resection of AJCC stage IIB, IIC and III cutaneous melanoma : an update

At present, there are no standard therapies for the adjuvant treatment of malignant melanoma. Patients with primary tumours with a high-Breslow thickness (stages IIB and IIC) or with resected loco-regional nodal disease (stage III) are at high risk of developing metastasis and subsequent disease-related death. Given this, it is important that novel therapies are investigated in the adjuvant melanoma setting. Since angiogenesis is essential for primary tumour growth and the development of metastasis, anti-angiogenic agents are attractive potential therapeutic candidates for clinical trials in the adjuvant setting. Therefore, we initiated a phase II trial in resected high-risk cutaneous melanoma, assessing the efficacy of bevacizumab versus observation. In the interim safety data analysis, we demonstrate that bevacizumab is a safe therapy in the adjuvant melanoma setting with no apparent increase in the surgical complication rate after either primary tumour resection and/or loco-regional lymphadenectomy

Clinical stakeholders' opinions on the use of selective decontamination of the digestive tract in critically ill patients in intensive care units : an international Delphi study

Peer reviewedPublisher PD

Atmospheric phase correction using CARMA-PACS: high angular resolution observations of the FU Orionis star PP 13S*

We present 0".15 resolution observations of the 227 GHz continuum emission from the circumstellar disk around the FU Orionis star PP 13S*. The data were obtained with the Combined Array for Research in Millimeter-wave Astronomy (CARMA) Paired Antenna Calibration System (C-PACS), which measures and corrects the atmospheric delay fluctuations on the longest baselines of the array in order to improve the sensitivity and angular resolution of the observations. A description of the C-PACS technique and the data reduction procedures are presented. C-PACS was applied to CARMA observations of PP 13S*, which led to a factor of 1.6 increase in the observed peak flux of the source, a 36% reduction in the noise of the image, and a 52% decrease in the measured size of the source major axis. The calibrated complex visibilities were fitted with a theoretical disk model to constrain the disk surface density. The total disk mass from the best-fit model corresponds to 0.06 M_⊙, which is larger than the median mass of a disk around a classical T Tauri star. The disk is optically thick at a wavelength of 1.3 mm for orbital radii less than 48 AU. At larger radii, the inferred surface density of the PP 13S* disk is an order of magnitude lower than that needed to develop a gravitational instability

The practical implications of using standardized estimation equations in calculating the prevalence of chronic kidney disease

BACKGROUND: Kidney Disease Outcomes Quality Initiative (KDOQI) chronic kidney disease (CKD) guidelines have focused on the utility of using the modified four-variable MDRD equation (now traceable by isotope dilution mass spectrometry IDMS) in calculating estimated glomerular filtration rates (eGFRs). This study assesses the practical implications of eGFR correction equations on the range of creatinine assays currently used in the UK and further investigates the effect of these equations on the calculated prevalence of CKD in one UK regionMETHODS: Using simulation, a range of creatinine data (30-300 micromol/l) was generated for male and female patients aged 20-100 years. The maximum differences between the IDMS and MDRD equations for all 14 UK laboratory techniques for serum creatinine measurement were explored with an average of individual eGFRs calculated according to MDRD and IDMS &lt; 60 ml/min/1.73 m(2) and 30 ml/min/1.73 m(2). Similar procedures were applied to 712,540 samples from patients &gt; or = 18 years (reflecting the five methods for serum creatinine measurement utilized in Northern Ireland) to explore, graphically, maximum differences in assays. CKD prevalence using both estimation equations was compared using an existing cohort of observed data.RESULTS: Simulated data indicates that the majority of laboratories in the UK have small differences between the IDMS and MDRD methods of eGFR measurement for stages 4 and 5 CKD (where the averaged maximum difference for all laboratory methods was 1.27 ml/min/1.73 m(2) for females and 1.59 ml/min/1.73 m(2) for males). MDRD deviated furthest from the IDMS results for the Endpoint Jaffe method: the maximum difference of 9.93 ml/min/1.73 m(2) for females and 5.42 ml/min/1.73 m(2) for males occurred at extreme ages and in those with eGFR &gt; 30 ml/min/1.73 m(2). Observed data for 93,870 patients yielded a first MDRD eGFR &lt; 60 ml/min/1.73 m(2) in 2001. 66,429 (71%) had a second test &gt; 3 months later of which 47,093 (71%) continued to have an eGFR &lt; 60 ml/min/1.73 m(2). Estimated crude prevalence was 3.97% for laboratory detected CKD in adults using the MDRD equation which fell to 3.69% when applying the IDMS equation. Over 95% of this difference in prevalence was explained by older females with stage 3 CKD (eGFR 30-59 ml/min/1.73 m(2)) close to the stage 2 CKD (eGFR 60-90 ml/min/1.73 m(2)) interface.CONCLUSIONS: Improved accuracy of eGFR is obtainable by using IDMS correction especially in the earlier stages of CKD 1-3. Our data indicates that this improved accuracy could lead to reduced prevalence estimates and potentially a decreased likelihood of onward referral to nephrology services particularly in older females.</p

Circulating tumor DNA predicts survival in patients with resected high risk stage II/III melanoma

Background: Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma. Patients and methods: We carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial. Results: Mutant BRAF or NRAS ctDNA was detected (≥1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval [DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79–5.47; P < 0.0001] and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80–5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83–5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88–6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%–55%) versus 65% (95% CI 56%–72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40–4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32–4.74, P = 0.005). Conclusion: ctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy

Near-Infrared Studies of V1280 Sco (Nova Scorpii 2007)

We present spectroscopic and photometric results of Nova V1280 Sco which was discovered in outburst in early 2007 February. The large number of spectra obtained of the object leads to one of the most extensive, near-infrared spectral studies of a classical nova. The spectra evolve from a P-Cygni phase to an emission-line phase and at a later stage is dominated by emission from the dust that formed in this nova. A detailed model is computed to identify and study characteristics of the spectral lines. Inferences from the model address the vexing question of which novae have the ability to form dust. It is demonstrated, and strikingly corroborated with observations, that the presence of lines in the early spectra of low-ionization species like Na and Mg - indicative of low temperature conditions - appear to be reliable indicators that dust will form in the ejecta. It is theoretically expected that mass loss during a nova outburst is a sustained process. Spectroscopic evidence for such a sustained mass loss, obtained by tracing the evolution of a P-Cygni feature in the Brackett gamma line, is presented here allowing a lower limit of 25-27 days to be set for the mass-loss duration. Photometric data recording the nova's extended 12 day climb to peak brightness after discovery is used to establish an early fireball expansion and also show that the ejection began well before maximum brightness. The JHK light curves indicate the nova had a fairly strong second outburst around 100 days after the first.Comment: Accepted in MNRAS. The paper contains 8 figures and 4 tables. Few typographical errors were correcte

The ethics of future trials: qualitative analysis of physicians' decision making

Background: The decision to conduct a randomized controlled trial (RCT) in a field raises ethical as well as scientific issues. From the clinical equipoise literature, future trials are justifiable if there is ”honest, professional disagreement in the community of expert practitioners as to the preferred treatment”. Empirical data are sparse about how clinicians apply the principles of equipoise to the justification of future RCTs. For example, selective decontamination of the digestive tract (SDD) is not widely used in critical care practice despite the strength of the evidence base and therefore provides a unique opportunity to learn how clinicians think about the ethics of further RCTs in critical care. Methods: In an international interview study of views of healthcare professionals about SDD, we undertook a secondary analysis of qualitative data collected using a Theoretical Domains Framework of clinical behaviour. We adopted a general descriptive approach to explore how physicians determined whether another RCT of SDD is ethical. Following a constant comparison approach, three investigators reviewed 54 purposively chosen transcripts from three international regions. We interpreted the data using thematic analysis. Results: We grouped participants’ responses into four inter-related themes: 1) cultural norms about evidence and practice within healthcare; 2) personal views about what evidence is current or applicable; 3) the interpersonal and relational nature of professional decision making locally; and 4) an a priori commitment to future trials. The analysis also identified several unresolved tensions regarding when a future RCT should be pursued. These tensions focused on a clash between potential benefits to current individual patients and potential future harms to patients more broadly. Conclusions: Our study suggests that ethical decision making about future RCTs in the field of SDD does not rely strongly on appeals to evidence, even when the quality of the evidence is reasonably high. Rather, “extra-evidential” reasons, including social, professional, and relational factors, seem to influence opinions regarding the ethics of future trials. Further work is required to see if these conclusions are applicable to other clinical topics and settings

Stretching the Rules: Monocentric Chromosomes with Multiple Centromere Domains

The centromere is a functional chromosome domain that is essential for faithful chromosome segregation during cell division and that can be reliably identified by the presence of the centromere-specific histone H3 variant CenH3. In monocentric chromosomes, the centromere is characterized by a single CenH3-containing region within a morphologically distinct primary constriction. This region usually spans up to a few Mbp composed mainly of centromere-specific satellite DNA common to all chromosomes of a given species. In holocentric chromosomes, there is no primary constriction; the centromere is composed of many CenH3 loci distributed along the entire length of a chromosome. Using correlative fluorescence light microscopy and high-resolution electron microscopy, we show that pea (Pisum sativum) chromosomes exhibit remarkably long primary constrictions that contain 3-5 explicit CenH3-containing regions, a novelty in centromere organization. In addition, we estimate that the size of the chromosome segment delimited by two outermost domains varies between 69 Mbp and 107 Mbp, several factors larger than any known centromere length. These domains are almost entirely composed of repetitive DNA sequences belonging to 13 distinct families of satellite DNA and one family of centromeric retrotransposons, all of which are unevenly distributed among pea chromosomes. We present the centromeres of Pisum as novel ``meta-polycentric'' functional domains. Our results demonstrate that the organization and DNA composition of functional centromere domains can be far more complex than previously thought, do not require single repetitive elements, and do not require single centromere domains in order to segregate properly. Based on these findings, we propose Pisum as a useful model for investigation of centromere architecture and the still poorly understood role of repetitive DNA in centromere evolution, determination, and function

Patient, health service factors and variation in mortality following resuscitated out-of-hospital cardiac arrest in acute coronary syndrome : analysis of the Myocardial Ischaemia National Audit Project

Aims To determine patient and health service factors associated with variation in hospital mortality among resuscitated cases of out-of-hospital cardiac arrest (OHCA) with acute coronary syndrome (ACS). Methods In this cohort study, we used the Myocardial Ischaemia National Audit Project database to study outcomes in patients hospitalised with resuscitated OHCA due to ACS between 2003 and 2015 in the United Kingdom. We analysed variation in inter-hospital mortality and used hierarchical multivariable regression models to examine the association between patient and health service factors with hospital mortality. Results We included 17604 patients across 239 hospitals. Overall hospital mortality was 28.7%. In 94 hospitals that contributed at least 60 cases, mortality by hospital ranged from 10.7% to 66.3% (median 28.6%, IQR 23.2% to 39.1%)). Patient and health service factors explained 36.1% of this variation. After adjustment for covariates, factors associated with higher hospital mortality included increasing serum glucose, ST-Elevation myocardial infarction (STEMI) diagnosis, and initial admission to a primary percutaneous coronary intervention (pPCI) capable hospital. Hospital OHCA volume was not associated with mortality. The key modifiable factor associated with lower mortality was early reperfusion therapy in STEMI patients. Conclusion There was wide variation in inter-hospital mortality following resuscitated OHCA due to ACS that was only partially explained by patient and health service factors. Hospital OHCA volume and pPCI capability were not associated with lower mortality. Early reperfusion therapy was associated with lower mortality in STEMI patients

Variation in outcome of hospitalised patients with out-of-hospital cardiac arrest from acute coronary syndrome : a cohort study

Background Each year, approximately 30,000 people have an out-of-hospital cardiac arrest (OHCA) that is treated by UK ambulance services. Across all cases of OHCA, survival to hospital discharge is less than 10%. Acute coronary syndrome (ACS) is a common cause of OHCA. Objectives To explore factors that influence survival in patients who initially survive an OHCA attributable to ACS. Data source Data collected by the Myocardial Ischaemia National Audit Project (MINAP) between 2003 and 2015. Participants Adult patients who had a first OHCA attributable to ACS and who were successfully resuscitated and admitted to hospital. Main outcome measures Hospital mortality, neurological outcome at hospital discharge, and time to all-cause mortality. Methods We undertook a cohort study using data from the MINAP registry. MINAP is a national audit that collects data on patients admitted to English, Welsh and Northern Irish hospitals with myocardial ischaemia. From the data set, we identified patients who had an OHCA. We used imputation to address data missingness across the data set. We analysed data using multilevel logistic regression to identify modifiable and non-modifiable factors that affect outcome. Results Between 2003 and 2015, 1,127,140 patient cases were included in the MINAP data set. Of these, 17,604 OHCA cases met the study inclusion criteria. Overall hospital survival was 71.3%. Across hospitals with at least 60 cases, hospital survival ranged from 34% to 89% (median 71.4%, interquartile range 60.7–76.9%). Modelling, which adjusted for patient and treatment characteristics, could account for only 36.1% of this variability. For the primary outcome, the key modifiable factors associated with reduced mortality were reperfusion treatment [primary percutaneous coronary intervention (pPCI) or thrombolysis] and admission under a cardiologist. Admission to a high-volume cardiac arrest hospital did not influence survival. Sensitivity analyses showed that reperfusion was associated with reduced mortality among patients with a ST elevation myocardial infarction (STEMI), but there was no evidence of a reduction in mortality in patients who did not present with a STEMI. Limitations This was an observational study, such that unmeasured confounders may have influenced study findings. Differences in case identification processes at hospitals may contribute to an ascertainment bias. Conclusions In OHCA patients who have had a cardiac arrest attributable to ACS, there is evidence of variability in survival between hospitals, which cannot be fully explained by variables captured in the MINAP data set. Our findings provide some support for the current practice of transferring resuscitated patients with a STEMI to a hospital that can deliver pPCI. In contrast, it may be reasonable to transfer patients without a STEMI to the nearest appropriate hospital. Future work There is a need for clinical trials to examine the clinical effectiveness and cost-effectiveness of invasive reperfusion strategies in resuscitated OHCA patients of cardiac cause who have not had a STEMI. Funding The National Institute for Health Research Health Services and Delivery Research programme