Comparison of the collagen haemostat Sangustop(R) versus a carrier-bound fibrin sealant during liver resection; ESSCALIVER-study

Background: Haemostasis in liver surgery remains a challenge despite improved resection techniques. Oozing from blood vessels too small to be ligated necessitate a treatment with haemostats in order to prevent complications attributed to bleeding. There is good evidence from randomised trials for the efficacy of fibrin sealants, on their own or in combination with a carrier material. A new haemostatic device is Sangustop(R). It is a collagen based material without any coagulation factors. Pre-clinical data for Sangustop(R) showed superior haemostatic effect. This present study aims to show that in the clinical situation Sangustop(R) is not inferior to a carrier-bound fibrin sealant (Tachosil(R)) as a haemostatic treatment in hepatic resection. Methods: This is a multi-centre, patient-blinded, intra-operatively randomised controlled trial. A total of 126 patients planned for an elective liver resection will be enrolled in eight surgical centres. The primary objective of this study is to show the non-inferiority of Sangustop(R) versus a carrier-bound fibrin sealant (Tachosil(R)) in achieving haemostasis after hepatic resection. The surgical intervention is standardised with regard to devices and techniques used for resection and primary haemostasis. Patients will be followed-up for three months for complications and adverse events. Discussion: This randomised controlled trial (ESSCALIVER) aims to compare the new collagen haemostat Sangustop(R) with a carrier-bound fibrin sealant which can be seen as a "gold standard" in hepatic and other visceral organ surgery. If non-inferiority is shown other criteria than the haemostatic efficacy (e.g. costs, adverse events rate) may be considered for the choice of the most appropriate treatment. Trial Registration: NCT0091861

Self-repair ability of evolved self-assembling systems in cellular automata

Self-repairing systems are those that are able to reconfigure themselves following disruptions to bring them back into a defined normal state. In this paper we explore the self-repair ability of some cellular automata-like systems, which differ from classical cellular automata by the introduction of a local diffusion process inspired by chemical signalling processes in biological development. The update rules in these systems are evolved using genetic programming to self-assemble towards a target pattern. In particular, we demonstrate that once the update rules have been evolved for self-assembly, many of those update rules also provide a self-repair ability without any additional evolutionary process aimed specifically at self-repair

Facilitating and motivating factors for reporting reprehensible conduct in care: A study among nurse practitioners and physician assistants in the Netherlands

Rationale, aims and objectives The aims of this study are as follows: (a) to establish whether a relationship exists between the importance that healthcare professionals attach to ethics in care and their likelihood to report reprehensible conduct committed by colleagues, and (b) to assess whether this relationship is moderated by behavioural control targeted at preventing harm. Method In this cross-sectional study, which was based on a convenience sample (n = 155) of nurse practitioners (NPs) and physician assistants (PAs) in the Netherlands, we measured ethics advocacy (EA) as a motivating factor (reflecting the importance that healthcare professionals attach to ethics and care) and "behavioral control targeted at preventing harm" (BCPH) as a facilitating factor. "Reporting reprehensible conduct" (RRC) was measured as a context-specific indicator of whistleblowing intentions, consisting of two vignettes describing morally questionable behaviour committed by colleagues. Results The propensity to report reprehensible conduct was a function of the interaction between EA and BCPH. The only group for which EA predicted RRC consisted of individuals with above-average levels of perceived BCPH. Conclusion The results suggest that the importance that healthcare professionals attach to ethical aspects in care is not sufficient to ensure that they will report reprehensible conduct. Such importance does not induce reporting behaviour unless the professionals also perceive themselves as having a high level of BCPH. We suggest that these insights could be helpful in training healthcare providers to cope with ethical dilemmas that they are likely to encounter in their work

Evaluation of stability of directly standardized rates for sparse data using simulation methods.

Background Directly standardized rates (DSRs) adjust for different age distributions in different populations and enable, say, the rates of disease between the populations to be directly compared. They are routinely published but there is concern that a DSR is not valid when it is based on a “small” number of events. The aim of this study was to determine the value at which a DSR should not be published when analyzing real data in England. Methods Standard Monte Carlo simulation techniques were used assuming the number of events in 19 age groups (i.e., 0–4, 5–9, ... 90+ years) follow independent Poisson distributions. The total number of events, age specific risks, and the population sizes in each age group were varied. For each of 10,000 simulations the DSR (using the 2013 European Standard Population weights), together with the coverage of three different methods (normal approximation, Dobson, and Tiwari modified gamma) of estimating the 95% confidence intervals (CIs), were calculated. Results The normal approximation was, as expected, not suitable for use when fewer than 100 events occurred. The Tiwari method and the Dobson method of calculating confidence intervals produced similar estimates and either was suitable when the expected or observed numbers of events were 10 or greater. The accuracy of the CIs was not influenced by the distribution of the events across categories (i.e., the degree of clustering, the age distributions of the sampling populations, and the number of categories with no events occurring in them). Conclusions DSRs should not be given when the total observed number of events is less than 10. The Dobson method might be considered the preferred method due to the formulae being simpler than that of the Tiwari method and the coverage being slightly more accurate

Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria

BACKGROUND: Treatments for uncomplicated falciparum malaria should have high cure rates. The World Health Organization has recently set a target cure rate of 95% assessed at 28 days. The use of more effective drugs, with longer periods of patient follow-up, and parasite genotyping to distinguish recrudescence from reinfection raise issues related to the design and interpretation of antimalarial treatment trials in uncomplicated falciparum malaria which are discussed here. METHODS: The importance of adequate follow-up is presented and the advantages and disadvantages of non-inferiority trials are discussed. The different methods of interpreting trial results are described, and the difficulties created by loss to follow-up and missing or indeterminate genotyping results are reviewed. CONCLUSION: To characterize cure rates adequately assessment of antimalarial drug efficacy in uncomplicated malaria requires a minimum of 28 days and as much as 63 days follow-up after starting treatment. The longer the duration of follow-up in community-based assessments, the greater is the risk that this will be incomplete, and in endemic areas, the greater is the probability of reinfection. Recrudescence can be distinguished from reinfection using PCR genotyping but there are commonly missing or indeterminate results. There is no consensus on how these data should be analysed, and so a variety of approaches have been employed. It is argued that the correct approach to analysing antimalarial drug efficacy assessments is survival analysis, and patients with missing or indeterminate PCR results should either be censored from the analysis, or if there are sufficient data, results should be adjusted based on the identified ratio of new infections to recrudescences at the time of recurrent parasitaemia. Where the estimated cure rates with currently recommended treatments exceed 95%, individual comparisons with new regimens should generally be designed as non-inferiority trials with sample sizes sufficient to determine adequate precision of cure rate estimates (such that the lower 95% confidence interval bound exceeds 90%)

Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies

There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented

Performance of Small Cluster Surveys and the Clustered LQAS Design to estimate Local-level Vaccination Coverage in Mali

<p>Abstract</p> <p>Background</p> <p>Estimation of vaccination coverage at the local level is essential to identify communities that may require additional support. Cluster surveys can be used in resource-poor settings, when population figures are inaccurate. To be feasible, cluster samples need to be small, without losing robustness of results. The clustered LQAS (CLQAS) approach has been proposed as an alternative, as smaller sample sizes are required.</p> <p>Methods</p> <p>We explored (i) the efficiency of cluster surveys of decreasing sample size through bootstrapping analysis and (ii) the performance of CLQAS under three alternative sampling plans to classify local VC, using data from a survey carried out in Mali after mass vaccination against meningococcal meningitis group A.</p> <p>Results</p> <p>VC estimates provided by a 10 × 15 cluster survey design were reasonably robust. We used them to classify health areas in three categories and guide mop-up activities: i) health areas not requiring supplemental activities; ii) health areas requiring additional vaccination; iii) health areas requiring further evaluation. As sample size decreased (from 10 × 15 to 10 × 3), standard error of VC and ICC estimates were increasingly unstable. Results of CLQAS simulations were not accurate for most health areas, with an overall risk of misclassification greater than 0.25 in one health area out of three. It was greater than 0.50 in one health area out of two under two of the three sampling plans.</p> <p>Conclusions</p> <p>Small sample cluster surveys (10 × 15) are acceptably robust for classification of VC at local level. We do not recommend the CLQAS method as currently formulated for evaluating vaccination programmes.</p

Overstating the evidence - double counting in meta-analysis and related problems

Background: The problem of missing studies in meta-analysis has received much attention. Less attention has been paid to the more serious problem of double counting of evidence. Methods: Various problems in overstating the precision of results from meta-analyses are described and illustrated with examples, including papers from leading medical journals. These problems include, but are not limited to, simple double-counting of the same studies, double counting of some aspects of the studies, inappropriate imputation of results, and assigning spurious precision to individual studies. Results: Some suggestions are made as to how the quality and reliability of meta-analysis can be improved. It is proposed that the key to quality in meta-analysis lies in the results being transparent and checkable. Conclusions: Existing quality check lists for meta-analysis do little to encourage an appropriate attitude to combining evidence and to statistical analysis. Journals and other relevant organisations should encourage authors to make data available and make methods explicit. They should also act promptly to withdraw meta-analyses when mistakes are found

The ACUTE (Ambulance CPAP: Use, Treatment effect and economics) feasibility study: a pilot randomised controlled trial of prehospital CPAP for acute respiratory failure

Background: Acute respiratory failure (ARF) is a common and life-threatening medical emergency. Standard prehospital management involves controlled oxygen therapy and disease-specific ancillary treatments. Continuous positive airway pressure (CPAP) is a potentially beneficial alternative treatment that could be delivered by emergency medical services. However, it is uncertain whether this treatment could work effectively in United Kingdom National Health Service (NHS) ambulance services and if it represents value for money. Methods: An individual patient randomised controlled external pilot trial will be conducted comparing prehospital CPAP to standard oxygen therapy for ARF. Adults presenting to ambulance service clinicians will be eligible if they have respiratory distress with peripheral oxygen saturation below British Thoracic Society (BTS) target levels, despite titrated supplemental oxygen. Enrolled patients will be allocated (1:1 simple randomisation) to prehospital CPAP (O_two system) or standard oxygen therapy using identical sealed boxes. Feasibility outcomes will include incidence of recruited eligible patients, number of erroneously recruited patients and proportion of cases adhering to allocation schedule and treatment, followed up at 30 days and with complete data collection. Effectiveness outcomes will comprise survival at 30 days (definitive trial primary end point), endotracheal intubation, admission to critical care, length of hospital stay, visual analogue scale (VAS) dyspnoea score, EQ-5D-5L and health care resource use at 30 days. The cost-effectiveness of CPAP, and of conducting a definitive trial, will be evaluated by updating an existing economic model. The trial aims to recruit 120 patients over 12 months from four regional ambulance hubs within the West Midlands Ambulance Service (WMAS). This sample size will allow estimation of feasibility outcomes with a precision of < 5%. Feasibility and effectiveness outcomes will be reported descriptively for the whole trial population, and each trial arm, together with their 95% confidence intervals. Discussion: This study will determine if it is feasible, acceptable and cost-effective to undertake a full-scale trial comparing CPAP and standard oxygen treatment, delivered by ambulance service clinicians for ARF. This will inform NHS practice and prevent inappropriate prehospital CPAP adoption on the basis of limited evidence and at a potentially substantial cost. Trial registration: ISRCTN12048261. Registered on 30 August 2017. http://www.isrctn.com/ISRCTN1204826