Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study

Background
Among clinical trials of interventions that aim to modify time spent on mechanical ventilation for critically ill patients there is considerable inconsistency in chosen outcomes and how they are measured. The Core Outcomes in Ventilation Trials (COVenT) study aims to develop a set of core outcomes for use in future ventilation trials in mechanically ventilated adults and children.

Methods/design
We will use a mixed methods approach that incorporates a randomised trial nested within a Delphi study and a consensus meeting. Additionally, we will conduct an observational cohort study to evaluate uptake of the core outcome set in published studies at 5 and 10 years following core outcome set publication. The three-round online Delphi study will use a list of outcomes that have been reported previously in a review of ventilation trials. The Delphi panel will include a range of stakeholder groups including patient support groups. The panel will be randomised to one of three feedback methods to assess the impact of the feedback mechanism on subsequent ranking of outcomes. A final consensus meeting will be held with stakeholder representatives to review outcomes.

Discussion
The COVenT study aims to develop a core outcome set for ventilation trials in critical care, explore the best Delphi feedback mechanism for achieving consensus and determine if participation increases use of the core outcome set in the long term.

Progress on core outcomes sets for critical care research

Purpose of review: Appropriate selection and definition of outcome measures are essential for clinical trials to be maximally informative. Core outcome sets (an agreed, standardized collection of outcomes measured and reported in all trials for a specific clinical area) were developed due to established inconsistencies in trial outcome selection. This review discusses the rationale for, and methods of, core outcome set development, as well as current initiatives in critical care.

Recent findings: Recent systematic reviews of reported outcomes and measurement instruments relevant to the critically ill highlight inconsistencies in outcome selection, definition, and measurement, thus establishing the need for core outcome sets. Current critical care initiatives include development of core outcome sets for trials aimed at reducing mechanical ventilation duration; rehabilitation following critical illness; long-term outcomes in acute respiratory failure; and epidemic and pandemic studies of severe acute respiratory infection.

Summary: Development and utilization of core outcome sets for studies relevant to the critically ill is in its infancy compared to other specialties. Notwithstanding, core outcome set development frameworks and guidelines are available, several sets are in various stages of development, and there is strong support from international investigator-led collaborations including the International Forum for Acute Care Trialists.

'Talk to me': a mixed methods study on preferred physician behaviours during end-of-life communication from the patient perspective

Background
Despite the recognized importance of end-of-life (EOL) communication between patients and physicians, the extent and quality of such communication is lacking.

Objective
We sought to understand patient perspectives on physician behaviours during EOL communication.

Design
In this mixed methods study, we conducted quantitative and qualitative strands and then merged data sets during a mixed methods analysis phase. In the quantitative strand, we used the quality of communication tool (QOC) to measure physician behaviours that predict global rating of satisfaction in EOL communication skills, while in the qualitative strand we conducted semi-structured interviews. During the mixed methods analysis, we compared and contrasted qualitative and quantitative data.

Setting and Participants
Seriously ill inpatients at three tertiary care hospitals in Canada.

Results
We found convergence between qualitative and quantitative strands: patients desire candid information from their physician and a sense of familiarity. The quantitative results (n = 132) suggest a paucity of certain EOL communication behaviours in this seriously ill population with a limited prognosis. The qualitative findings (n = 16) suggest that at times, physicians did not engage in EOL communication despite patient readiness, while sometimes this may represent an appropriate deferral after assessment of a patient's lack of readiness.

Conclusions
Avoidance of certain EOL topics may not always be a failure if it is a result of an assessment of lack of patient readiness. This has implications for future tool development: a measure could be built in to assess whether physician behaviours align with patient readiness.

Capsulotomy worsens diabetic retinopathy in the Ins2Akitamice

Purpose: Cataract surgery increases the risk of developing diabetic retinopathy (DR) and accelerates the progression of pre-existing DR. Recent evidence suggests that cataract surgery elicits retinal pro-inflammatory gene expression, although the underlying pathogenic mechanisms remain ill-defined. In this study, we investigated the effect of capsulotomy on visual function, retinal immune cell activation and photoreceptor stress in the Ins2Akita mice, a mouse model of Type-1 diabetes. Methods: Male heterozygous Ins2Akita mice (2 months of hyperglycemia) and C57BL/6J age-matched siblings were used in this study. An incision (1mm) was made in the peripheral cornea and Capsulotomy was performed in the anterior lens capsule of the right eye. Control mice received corneal incision without capsulotomy in the right eye. The unoperated left eyes were used as internal controls. Forty days following surgery, retinal function was assessed by electroretinography (ERG). Neuronal retinal damage and microglial activation were assessed by imunohistochemistry. Results: The Ins2Akita mice receiving capsulotomy presented lower scotopic a-wave, b-wave and oscillatory potentials amplitudes compared to other experimental groups. Fundus images, SD-OCT and H&E staining did not show significant changes between different groups. Immunostaining of Iba-1 and CD68 revealed exacerbated microglial activation and giant cell immune cell infiltration in eyes receiving capsulotomy in Ins2Akita mice. This was accompanied by a disruption of cone photoreceptor outer segments and abnormal rhodopsin expression at the outer nuclear layer. Conclusions: Our results suggest that capsulotomy induces retinal microglial activation and worsens retinal neuropathy in diabetic eyes.

Multiloop robust H∞ control design based on the dynamic PLS approach to chemical processes

In this paper, a multiloop robust control strategy is proposed based on H∞ control and a partial least squares (PLS) model (H∞_PLS) for multivariable chemical processes. It is developed especially for multivariable systems in ill-conditioned plants and non-square systems. The advantage of PLS is to extract the strongest relationship between the input and the output variables in the reduced space of the latent variable model rather than in the original space of the highly dimensional variables. Without conventional decouplers, the dynamic PLS framework automatically decomposes the MIMO process into multiple single-loop systems in the PLS subspace so that the controller design can be simplified. Since plant/model mismatch is almost inevitable in practical applications, to enhance the robustness of this control system, the controllers based on the H∞ mixed sensitivity problem are designed in the PLS latent subspace. The feasibility and the effectiveness of the proposed approach are illustrated by the simulation results of a distillation column and a mixing tank process. Comparisons between H∞_PLS control and conventional individual control (either H∞ control or PLS control only) are also made

The E3 ubiquitin ligase Pellino3 protects against obesity-induced inflammation and insulin resistance

Diet-induced obesity can induce low-level inflammation and insulin resistance. Interleukin-1β (IL-1β) is one of the key proinflammatory cytokines that contributes to the generation of insulin resistance and diabetes, but the mechanisms that regulate obesity-driven inflammation are ill defined. Here we found reduced expression of the E3 ubiquitin ligase Pellino3 in human abdominal adipose tissue from obese subjects and in adipose tissue of mice fed a high-fat diet and showing signs of insulin resistance. Pellino3-deficient mice demonstrated exacerbated high-fat-diet-induced inflammation, IL-1β expression, and insulin resistance. Mechanistically, Pellino3 negatively regulated TNF receptor associated 6 (TRAF6)-mediated ubiquitination and stabilization of hypoxia-inducible factor 1α (HIF1α), resulting in reduced HIF1α-induced expression of IL-1β. Our studies identify a regulatory mechanism controlling diet-induced insulin resistance by highlighting a critical role for Pellino3 in regulating IL-1β expression with implications for diseases like type 2 diabetes.

Trends and Determinants of Work-Retirement Transitions under Changing Institutional Conditions: Germany, England and Japan compared

Many governments world-wide are promoting longer working life due to the social and economic repercussions of demographic change. However, not all workers are equally able to extend their employment careers. Thus, while national policies raise the overall level of labour market participation, they might create new social and labour market inequalities. This paper explores how institutional differences in the United Kingdom, Germany and Japan affect individual retirement decisions on the aggregate level, and variations in individuals’ degree of choice within and across countries. We investigate which groups of workers are disproportionately at risk of being ‘pushed’ out of employment, and how such inequalities have changed over time. We use comparable national longitudinal survey datasets focusing on the older population in England, Germany and Japan. Results point to cross-national differences in retirement transitions. Retirement transitions in Germany have occurred at an earlier age than in England and Japan. In Japan, the incidence of involuntary retirement is the lowest, reflecting an institutional context prescribing that employers provide employment until pension age, while Germany and England display substantial proportions of involuntary exits triggered by organisational-level redundancies, persistent early retirement plans or individual ill-health.

A realistic evaluation of track and trigger systems and acute care training for early recognition and treatment of deteriorating ward-based patients: research protocol.

Aim The aim of the study is to evaluate factors that enable or constrain the implementation and service delivery of early warnings systems or acute care training in practice. Background To date there is limited evidence to support the effectiveness of acute care initiatives (early warning systems, acute care training, outreach) in reducing the number of adverse events (cardiac arrest, death, unanticipated Intensive Care admission) through increased recognition and management of deteriorating ward based patients in hospital [1-3]. The reasons posited are that previous research primarily focused on measuring patient outcomes following the implementation of an intervention or programme without considering the social factors (the organisation, the people, external influences) which may have affected the process of implementation and hence measured end-points. Further research which considers the social processes is required in order to understand why a programme works, or does not work, in particular circumstances [4]. Method The design is a multiple case study approach of four general wards in two acute hospitals where Early Warning Systems (EWS) and Acute Life-threatening Events Recognition and Treatment (ALERT) course have been implemented. Various methods are being used to collect data about individual capacities, interpersonal relationships and institutional balance and infrastructures in order to understand the intended and unintended process outcomes of implementing EWS and ALERT in practice. This information will be gathered from individual and focus group interviews with key participants (ALERT facilitators, nursing and medical ALERT instructors, ward managers, doctors, ward nurses and health care assistants from each hospital); non-participant observation of ward organisation and structure; audit of patients' EWS charts and audit of the medical notes of patients who deteriorated during the study period to ascertain whether ALERT principles were followed. Discussion & progress to date This study commenced in January 2007. Ethical approval has been granted and data collection is ongoing with interviews being conducted with key stakeholders. The findings from this study will provide evidence for policy-makers to make informed decisions regarding the direction for strategic and service planning of acute care services to improve the level of care provided to acutely ill patients in hospital. References 1. Esmonde L, McDonnell A, Ball C, Waskett C, Morgan R, Rashidain A et al. Investigating the effectiveness of Critical Care Outreach Services: A systematic review. Intensive Care Medicine 2006; 32: 1713-1721 2. McGaughey J, Alderdice F, Fowler R, Kapila A, Mayhew A, Moutray M. Outreach and Early Warning Systems for the prevention of Intensive Care admission and death of critically ill patients on general hospital wards. Cochrane Database of Systematic Reviews 2007, Issue 3. www.thecochranelibrary.com 3. Winters BD, Pham JC, Hunt EA, Guallar E, Berenholtz S, Pronovost PJ (2007) Rapid Response Systems: A systematic review. Critical Care Medicine 2007; 35 (5): 1238-43 4. Pawson R and Tilley N. Realistic Evaluation. London; Sage: 1997

Evidence-based practice: the relevance of systematic reviews.

Aim:
To demonstrate how systematic reviews provide robust evidence to inform clinical decision making in practice.

Background
Systematic reviews collate findings from a number of research studies in order to provide a comprehensive and reliable summary of the best available evidence. The use of systematic reviews to inform practice based decisions has increased as a result of the overwhelming amount of research literature available, poor quality of research evidence and the need to ensure practice is based upon the best available evidence. Systematic reviews are an efficient way of coping with large volumes of data to answer focused research questions. They differ from traditional literature reviews as they adhere to an explicit scientific process. The use of explicit and rigorous methods to identify, appraise and synthesise relevant studies minimises bias and provides a reliable basis for decision making. As a result systematic reviews provide clear evidence on the effectiveness of a healthcare intervention to inform policy and decision making across healthcare systems. An example of how the findings from systematic reviews can provide reliable evidence to inform healthcare decisions will be provided in this presentation1. This will demonstrate how focused clinical questions can be answered by systematic reviews and translated into practice.

Reference:
1. McGaughey J, Alderdice F, Fowler R, Kapila A, Moutray M. (2007) Outreach and Early Warning Systems (EWS) for the prevention of Intensive Care admission admission and death of critically ill adult patients on general hospital wards (REVIEW). The Cochrane Database of Systematic Reviews 3. art no CD005529

Protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in newborn infants: review

Background
Mechanical ventilation is a life-saving intervention for critically ill newborn infants with respiratory failure admitted to a neonatal intensive care unit (NICU). Ventilating newborn infants can be challenging due to small tidal volumes, high breathing frequencies, and the use of uncuffed endotracheal tubes. Mechanical ventilation has several short-term, as well as long-term complications. To prevent complications, weaning from the ventilator is started as soon as possible. Weaning aims to support the transfer from full mechanical ventilation support to spontaneous breathing activity.

Objectives
To assess the efficacy of protocolized versus non-protocolized ventilator weaning for newborn infants in reducing the duration of invasive mechanical ventilation, the duration of weaning, and shortening the NICU and hospital length of stay. To determine efficacy in predefined subgroups including: gestational age and birth weight; type of protocol; and type of protocol delivery. To establish whether protocolized weaning is safe and clinically effective in reducing the duration of mechanical ventilation without increasing the risk of adverse events.

Search methods
We searched the Cochrane Central Register of Controlled trials (CENTRAL; the Cochrane Library; 2015, Issue 7); MEDLINE In-Process and other Non-Indexed Citations and OVID MEDLINE (1950 to 31 July 2015); CINAHL (1982 to 31 July 2015); EMBASE (1988 to 31 July 2015); and Web of Science (1990 to 15 July 2015). We did not restrict language of publication. We contacted authors of studies with a subgroup of newborn infants in their study, and experts in the field regarding this subject. In addition, we searched abstracts from conference proceedings, theses, dissertations, and reference lists of all identified studies for further relevant studies.

Selection criteria
Randomized, quasi-randomized or cluster-randomized controlled trials that compared protocolized with non-protocolized ventilator weaning practices in newborn infants with a gestational age of 24 weeks or more, who were enrolled in the study before the postnatal age of 28 completed days after the expected date of birth.

Data collection and analysis
Four authors, in pairs, independently reviewed titles and abstracts identified by electronic searches. We retrieved full-text versions of potentially relevant studies.

Main results
Our search yielded 1752 records. We removed duplicates (1062) and irrelevant studies (843). We did not find any randomized, quasi-randomized or cluster-randomized controlled trials conducted on weaning from mechanical ventilation in newborn infants. Two randomized controlled trials met the inclusion criteria on type of study and type of intervention, but only included a proportion of newborns. The study authors could not provide data needed for subgroup analysis; we excluded both studies.

Authors' conclusions
Based on the results of this review, there is no evidence to support or refute the superiority or inferiority of weaning by protocol over non-protocol weaning on duration of invasive mechanical ventilation in newborn infants.

Solid-liquid interfacial free energy out of equilibrium

The properties of the interface between solid and melt are key to solidification and melting, as the interfacial free energy introduces a kinetic barrier to phase transitions. This makes solidification happen below the melting temperature, in out-of-equilibrium conditions at which the interfacial free energy is ill defined. Here we draw a connection between the atomistic description of a diffuse solid-liquid interface and its thermodynamic characterization. This framework resolves the ambiguities in defining the solid-liquid interfacial free energy above and below the melting temperature. In addition, we introduce a simulation protocol that allows solid-liquid interfaces to be reversibly created and destroyed at conditions relevant for experiments. We directly evaluate the value of the interfacial free energy away from the melting point for a simple but realistic atomic potential, and find a more complex temperature dependence than the constant positive slope that has been generally assumed based on phenomenological considerations and that has been used to interpret experiments. This methodology could be easily extended to the study of other phase transitions, from condensation to precipitation. Our analysis can help reconcile the textbook picture of classical nucleation theory with the growing body of atomistic studies and mesoscale models of solidification.

Impacts of Milk Fraud on Food Safety and Nutrition with Special Emphasis on Developing Countries

Milk in its natural form has a high food value, since it is comprised of a wide variety of nutrients which are essential for proper growth and maintenance of the human body. In recent decades, there has been an upsurge in milk consumption worldwide, especially in developing countries, and it is now forming a significant part of the diet for a high proportion of the global population. As a result of the increased demand, in addition to the growth in competition in the dairy market and the increasing complexity of the supply chain, some unscrupulous producers are indulging in milk fraud. This malpractice has become a common problem in the developing countries, which lack strict vigilance by food safety authorities. Milk is often subjected to fraud (by means of adulteration) for financial gain, but it can also be adulterated due to ill-informed attempts to improve hygiene conditions. Water is the most common adulterant used, which decreases the nutritional value of milk. If the water is contaminated, for example, with chemicals or pathogens, this poses a serious health risk for consumers. To the diluted milk, inferior cheaper materials may be added such as reconstituted milk powder, urea, and cane sugar, even more hazardous chemicals including melamine, formalin, caustic soda, and detergents. These additions have the potential to cause serious health-related problems. This review aims to investigate the impacts of milk fraud on nutrition and food safety, and it points out the potential adverse human health effects associated with the consumption of adulterated milk.

A Largest Matching Area Approach to Image Denoising

Given the success of patch-based approaches to image denoising,this paper addresses the ill-posed problem of patch size selection.Large patch sizes improve noise robustness in the presence of good matches, but can also lead to artefacts in textured regions due to the rare patch effect; smaller patch sizes reconstruct details more accurately but risk over-fitting to the noise in uniform regions. We propose to jointly optimize each matching patch’s identity and size for gray scale image denoising, and present several implementations.The new approach effectively selects the largest matching areas, subject to the constraints of the available data and noise level, to improve noise robustness. Experiments on standard test images demonstrate our approach’s ability to improve on fixed-size reconstruction, particularly at high noise levels, on smoother image regions.

Do women who intermittently attend breast screening differ from those women who attend every invitation and those who never attend?

OBJECTIVES:

Analysis of screening uptake usually dichotomizes women into attenders and non-attenders, though many women respond positively to some but not all invitations. This paper studies these intermittent attenders.

METHODS:

A cohort of 8,571 women invited for consecutive breast screens in the Northern Ireland Breast Screening Programme were followed in a study linking screening and census records. Multivariate logistic analysis was used to analyze the characteristics of those who attended both times (consistent), once (intermittent or 'one-time only'), or not at all (non-attenders).

RESULTS:

Overall, 15.5% of women attended once and 13.4% were non-attenders. Non-attenders were characteristically disadvantaged (as measured by social renting, car access, and employment status), less likely to be married, and more likely to be healthy. One-time attenders were younger, and suffering poor health, though there was no association with either social renting or employment status. Privately rented accommodation and city living was associated with both one-time attendance and non-attendance.

CONCLUSIONS:

One-time attenders are an important and distinct subgroup of screening invitees in this analysis. Their distinct characteristics suggest that transitory factors, such as change in marital status, ill-health, or addressing difficulties through change of residence are important. These distinct characteristics suggest the need for different approaches to increase attendance, among both intermittent attenders and those not attending at all.

Housing, Regeneration and Community Asset Transfer

Community asset transfer enables local groups to own or manage a government owned facility and/or related services. For critics, it is merely an extension of roll-back neoliberalism, permitting the state to withdraw from welfare and transfer risk from local government to ill-defined communities. The paper uses quantitative and case study data from Northern Ireland to demonstrate its transformative potential by challenging the notion of private property rights, enabling communities to accumulate and endanger forms of cooperative consumption. It concludes by highlighting the implications for more progressive forms of social economics in relation to public and private markets and government sponsorship of its own development.